ASCI - Stem Cell Rejuvenation

Optic Nerve Injuries Stem Cell Treatment

 Stem Cells for Optic Nerve Injuries

 

 

 

Optic Nerve Injury Treatments using Stem Cells is now an option here in San Francisco, California USA.

Via IV and Retrobulbar injections of the patient's own Mesenchymal Stem Cells, we strive to give patients an option whereas there was none before. The optic nerve is composed of retinal ganglion cell axons and support cells. It leaves the orbit (eye socket) via the optic canal, running postero-medially towards the optic chiasm, where there is a partial decussation (crossing) of fibres from the nasal visual fields of both eyes. The optic nerve is the second of twelve paired cranial nerves but is considered to be part of the central nervous system, as it is derived from an outpouching of the diencephalon during embryonic development. As a consequence, the fibres are covered with myelin produced by oligodendrocytes, rather than Schwann cells, which are found in the peripheral nervous system, and are encased within the meninges.

Damage to the optic nerve typically causes permanent and potentially severe loss of vision, as well as an abnormal pupillary reflex, which is diagnostically important. The type of visual field loss will depend on which portions of the optic nerve were damaged. In general:

  • Damage proximal to the optic chiasm causes loss of vision in the visual field of the same side only.
  • Damage in the chiasm causes loss of vision laterally in both visual fields (bitemporal hemianopia). It may occur in large pituitary adenomata.
  • Damage distal to the chiasm causes loss of vision in one eye but affecting both visual fields: The visual field affected is located on the opposite side of the lesion.

Injury to the optic nerve can be the result of congenital or inheritable problems like Leber's Hereditary Optic Neuropathy, glaucoma, trauma, toxicity, inflammation, ischemia, infection (very rarely), or compression from tumors or aneurysms. By far, the three most common injuries to the optic nerve are from glaucoma, optic neuritis (especially in those younger than 50 years of age), and anterior ischemic optic neuropathy (usually in those older than 50).

  • Glaucoma is a group of diseases involving loss of retinal ganglion cells causing optic neuropathy in a pattern of peripheral vision loss, initially sparing central vision.
  • Optic neuritis is inflammation of the optic nerve. It is associated with a number of diseases, the most notable one being multiple sclerosis.
  • Anterior Ischemic Optic Neuropathy is a particular type of infarct that affects patients with an anatomical predisposition and cardiovascular risk factors.
  • Optic nerve hypoplasia is the under-development of the optic nerve causing little to no vision in the affected eye.

Our goal is to overcome the limitations that Optic Nerve Injuries have placed on our patients using Autologous Stem Cell Therapies.

Stem Cell Treatments for Optic Nerve Injury and Damage

Streaming NIH Search and Results:

{module Stem Cell Treatment Optic Nerve Injuries}


Stem Cell Treatment Optic Nerve Injuries
Related Articles GeneReviews(®) Book. 1993 Authors: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K Abstract DISEASE CHARACTERISTICS: The spectrum of CLCN7-related osteopetrosis includes infantile malignant CLCN7-related recessive osteopetrosis (ARO), intermediate autosomal osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII, Albers-Schoenberg disease). Onset of ARO is in infancy; findings may include fractures; poor growth; sclerosis of the skull base (with or without choanal stenosis or hydrocephalus) resulting in optic nerve compression, facial palsy, and hearing loss; absence of the bone marrow cavity resulting in severe anemia and thrombocytopenia; dental abnormalities, odontomas, and risk for mandibular osteomyelitis; and hypocalcemia with tetanic seizures and secondary hyperparathyroidism. Without treatment maximal life span in ARO is ten years. Onset of IAO is in childhood; findings may include fractures after minor trauma, characteristic skeletal radiographic changes found incidentally, mild anemia, and occasional visual impairment secondary to optic nerve compression. Life expectancy in IAO is usually normal. Onset of ADOII is usually late childhood or adolescence; findings may include fractures (in any long bone and/or the posterior arch of a vertebra); scoliosis; hip osteoarthritis; osteomyelitis of the mandible or septic osteitis or osteoarthritis elsewhere. Cranial nerve compression is rare. DIAGNOSIS/TESTING: Diagnosis of CLCN7-related osteopetrosis usually relies on radiographic changes that are pathognomonic in ARO (generalized osteosclerosis, club-shaped long bones, osteosclerosis of the skull base, bone-within-bone appearance) and characteristic in ADOII (osteosclerosis of the spine ("sandwich vertebra" appearance), bone-within-bone appearance (mainly iliac wings), Erlenmeyer-shaped femoral metaphysis, mild osteosclerosis of the skull base, transverse bands of osteosclerosis in long bones). CLCN7 is the only gene in which mutations are known to cause CLCN7-related osteopetrosis. MANAGEMENT: Treatment of manifestations: ARO. Calcium supplementation for hypocalcemic convulsions; management of calcium homeostasis per the individual’s needs; erythrocyte or platelet transfusions as needed; antibiotics for leukocytopenia; immunoglobulins for hypogammaglobulinemia; surgical decompression of the optic nerve; treatment of fractures by an experienced orthopedist; dental care with attention to tooth eruption, ankylosis, abscesses, cysts, fistulas. ADOII. Orthopedic treatment for fractures and arthritis with attention to potential post-surgical complications (delayed union or non-union of fractures, infection); fractures near joints may require total joint arthroplasty. Prevention of primary manifestations: ARO. Hematopoietic stem cell transplantation (HSCT) can be curative; however, cranial nerve dysfunction is usually irreversible, and progressive neurologic sequelae occur in children with the neuronopathic form even after successful HSCT. Prevention of secondary complications: ARO. Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia. ADOII. Good routine dental care and oral hygiene to help prevent osteomyelitis of the mandible. Surveillance: ARO. Complete blood count and ophthalmologic examination at least once a year; follow-up per the transplantation center following HSCT. Agents/circumstances to avoid: ADOII. Activities with high fracture risk. GENETIC COUNSELING: ARO is inherited in an autosomal recessive manner; ADOII is inherited in an autosomal dominant manner; about 40% of IAO is inherited in an autosomal recessive manner and about 60% in an autosomal dominant manner. Autosomal recessive inheritance. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Individuals with ARO in general only reproduce if successfully treated by HSCT. Autosomal dominant inheritance. Most individuals diagnosed with autosomal dominant CLCN7-related osteopetrosis have an affected parent. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with autosomal dominant CLCN7-related osteopetrosis has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk for ADOII and ARO is possible if the disease-causing mutation(s) has/have been identified in the family. PMID: 20301306
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Related Articles Multiple intracranial meningiomas causing papilledema and visual loss in a patient with nevoid Basal cell carcinoma syndrome. J Neuroophthalmol. 2008 Mar;28(1):41-6 Authors: Pribila JT, Ronan SM, Trobe JD Abstract A 27-year-old man with nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) who had undergone craniospinal irradiation for a childhood brain stem medulloblastoma complained of progressive binocular visual loss. Ophthalmologic examination disclosed subnormal visual acuity and visual fields in both eyes attributed to chronic papilledema. Brain MRI demonstrated mass effect from multiple large meningiomas. After embolization and surgical resection of the largest meningioma, papilledema disappeared and visual dysfunction resolved partially. This is the sixth reported patient with NBCCS, medulloblastoma, and craniospinal radiation who has developed intracranial meningioma, further documenting the fact that such patients have a relatively high likelihood of developing meningiomas, especially multiple meningiomas. Because patients with NBCCS are often mentally impaired and because papilledema can progress silently before causing irreversible visual loss, periodic ophthalmologic examination is advisable after craniospinal radiation. PMID: 18347458 [PubMed - indexed for MEDLINE]
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Related Articles Predictive factors for vision loss after hematopoietic cell transplant for X-linked adrenoleukodystrophy. J AAPOS. 2008 Jun;12(3):273-6 Authors: Gess A, Christiansen SP, Pond D, Peters C Abstract BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is an inherited disease characterized by cerebral demyelination, adrenal insufficiency, and progressive neurological deterioration. Hematopoietic cell transplantation (HCT) is the only effective treatment. Visual dysfunction is a common component of the disease and may continue to progress in patients after HCT. This study was designed to determine prognostic factors predictive of vision loss after HCT. SUBJECTS AND METHODS: A retrospective chart review was performed for all boys who had HCT for cerebral X-ALD at the University of Minnesota between 1991 and 2002. Patients were included if they survived 100 days post-HCT and had pre- and post-HCT ophthalmology evaluation. Complete data were available for 14 patients. Patient characteristics examined included HLA match status, graft-versus-host disease prophylaxis, source of HCT, reason for diagnosis, age at treatment, magnetic resonance imaging (MRI) severity score, pattern of demyelination on MRI, and pretreatment performance intelligence quotient (IQ). Univariate analysis was performed for correlation with posttransplant visual acuity and optic disk pallor. RESULTS: Factors significantly correlated with loss of visual acuity after HCT included pretransplant MRI severity score >11 (p = 0.03), pretransplant performance IQ <76 (p = 0.02), and the presence of pretransplant parieto-occipital demyelination on MRI (p = 0.03). Additionally, the presence of pretransplant parieto-occipital demyelination on MRI was found to correlate with the development of new optic disk pallor after HCT (p = 0.05). CONCLUSIONS: This study identifies patient characteristics predictive of vision loss after HCT for X-ALD. Decisions about treatment for X-ALD rely heavily upon prognostic information about adverse outcomes following HCT. These findings will aid clinicians counseling patients considering HCT for X-ALD. PMID: 18359652 [PubMed - indexed for MEDLINE]
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Related Articles Engrafted chicken neural tube-derived stem cells support the innate propensity for axonal regeneration within the rat optic nerve. Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3513-24 Authors: Charalambous P, Hurst LA, Thanos S Abstract PURPOSE: Injury to the adult optic nerve, caused mechanically or by diseases, is still not reparable because the retinal ganglion cells (RGCs) are not allowed to regrow their axons and die retrogradely, although they possess the intrinsic propensity to regenerate axons in experimental conditions. METHODS: In vitro propagated embryonic stem cells derived from the early chicken neural tube (NTSCs) were used to examine whether transplanted NTSCs produce growth-promoting factors and pave the microenvironment, thus facilitating axonal regeneration within the rat optic nerve. RESULTS: NTSCs survived within the site where the optic nerve had been cut and continued to be nestin-positive, thus preserving their undifferentiated cell phenotype. Transplanted NTSCs activated the matrix metalloproteases (MMP)-2 and -14 in glial fibrillary acidic protein (GFAP)-positive optic nerve astrocytes. MMP2 production correlated with immunohistochemically visible degradation of inhibitory chondroitin sulfate proteoglycans (CSPGs). In addition, NTSCs produced a panoply of neurite-promoting factors including oncomodulin, ciliary neurotrophic factor, brain-derived neurotrophic factor and crystallins beta and gamma. Cut axons intermingled with NTSCs and passed through the zone of injury to enter the distal optic nerve over long distances, arriving at the thalamus and midbrain. CONCLUSIONS: This study showed evidence that paving of the distal optic nerve microenvironment with proteolytically active MMPs and providing stem-cell-derived growth factors is a suitable method for facilitating regenerative repair of the optic nerve. Understanding the molecular mechanisms of this repair has fundamental implications for development of NTSC-based subsidiary therapy after neural injuries. PMID: 18408190 [PubMed - indexed for MEDLINE]
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Related Articles Purification of oligodendrocytes and their progenitors using immunomagnetic separation and Percoll gradient centrifugation. Curr Protoc Neurosci. 2001 May;Chapter 3:Unit 3.12 Authors: Colello RJ, Sato-Bigbee C Abstract In this unit, two techniques are described for the purification of oligodendrocytes and their progenitors from the developing mammalian central nervous system (CNS). The first method utilizes the technique of immunomagnetic separation to selectively isolate oligodendrocytes and their progenitor cells from the optic nerve of prenatal and early postnatal rats. This technique takes advantage of the surface antigens expressed on these cells. A paramagnetic bead is attached to the cells via an antibody bridge. Target cells that are coupled to magnetic beads can then be separated from a heterogeneous cell population using a magnetic field. The second method for isolating oligodendrocytes uses Percoll gradient centrifugation to separate oligodendrocytes from a heterogeneous cell population by virtue of their cell density and allows the direct isolation of oligodendrocytes from animals aged postnatal day 4 (P-4) to adult. This method is particularly useful for assessing physiological systems present in development that may be lost as a result of growing purified neonatal cells in vitro in the absence of neuronal influence. PMID: 18428461 [PubMed - indexed for MEDLINE]
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Related Articles Isolation and purification of primary rodent astrocytes. Curr Protoc Neurosci. 2001 May;Chapter 3:Unit 3.5 Authors: Weinstein DE Abstract Astrocytes are a major cell type in the mammalian central nervous system (CNS). The ability to obtain virtually pure populations of these cells makes it possible to study their function as isolated cells or in mixed populations where they support the growth and survival of surrounding neurons. Unlike other mature CNS cells, mature astrocytes maintain the lifelong ability to reenter the cell cycle. The first isolation procedure described in this unit takes advantage of the proliferative ability of these cells, as does the second, except that no antibody or complement treatment is required. A procedure for detecting glial fibrillary acidic protein (GFAP), which is present in most astrocytes in vivo and virtually all astrocytes in vitro and is a useful marker for assessing the purity of cultures, is also presented. PMID: 18428469 [PubMed - indexed for MEDLINE]
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Related Articles Molecular and cell-based approaches for neuroprotection in glaucoma. Optom Vis Sci. 2008 Jun;85(6):417-24 Authors: Lebrun-Julien F, Di Polo A Abstract A hallmark of glaucomatous optic nerve damage is retinal ganglion cell (RGC) death. RGCs, like other central nervous system neurons, have a limited capacity to survive or regenerate an axon after injury. Strategies that prevent or slow down RGC degeneration, in combination with intraocular pressure management, may be beneficial to preserve vision in glaucoma. Recent progress in neurobiological research has led to a better understanding of the molecular pathways that regulate the survival of injured RGCs. Here we discuss a variety of experimental strategies including intraocular delivery of neuroprotective molecules, viral-mediated gene transfer, cell implants and stem cell therapies, which share the ultimate goal of promoting RGC survival after optic nerve damage. The challenge now is to assess how this wealth of knowledge can be translated into viable therapies for the treatment of glaucoma and other optic neuropathies. PMID: 18521011 [PubMed - indexed for MEDLINE]
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Related Articles Neural regeneration and cell replacement: a view from the eye. Cell Stem Cell. 2008 Jun 5;2(6):538-49 Authors: Lamba D, Karl M, Reh T Abstract Neuronal degenerations in the retina are leading causes of blindness. Like most other areas of the CNS, the neurons of the mammalian retina are not replaced following degeneration. However, in nonmammalian vertebrates, endogenous repair processes restore neurons very efficiently, even after complete loss of the retina. We describe the phenomenon of retinal regeneration in nonmammalian vertebrates and attempts made in recent years to stimulate similar regenerative processes in the mammalian retina. In addition, we review the various strategies employed to replace lost neurons in the retina and the recent use of stem cell technologies to address problems of retinal repair. PMID: 18522847 [PubMed - indexed for MEDLINE]
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Related Articles Bone marrow-derived mesenchymal stem cell transplantation does not improve quality of muscle reinnervation or recovery of motor function after facial nerve transection in rats. Biol Chem. 2008 Jul;389(7):873-88 Authors: Grosheva M, Guntinas-Lichius O, Arnhold S, Skouras E, Kuerten S, Streppel M, Angelova SK, Wewetzer K, Radtke C, Dunlop SA, Angelov DN Abstract Recently, we devised and validated a novel strategy in rats to improve the outcome of facial nerve reconstruction by daily manual stimulation of the target muscles. The treatment resulted in full recovery of facial movements (whisking), which was achieved by reducing the proportion of pathologically polyinnervated motor endplates. Here, we posed whether manual stimulation could also be beneficial after a surgical procedure potentially useful for treatment of large peripheral nerve defects, i.e., entubulation of the transected facial nerve in a conduit filled with suspension of isogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) in collagen. Compared to control treatment with collagen only, entubulation with BM-MSCs failed to decrease the extent of collateral axonal branching at the lesion site and did not improve functional recovery. Post-operative manual stimulation of vibrissal muscles also failed to promote a better recovery following entubulation with BM-MSCs. We suggest that BM-MSCs promote excessive trophic support for regenerating axons which, in turn, results in excessive collateral branching at the lesion site and extensive polyinnervation of the motor endplates. Furthermore, such deleterious effects cannot be overridden by manual stimulation. We conclude that entubulation with BM-MSCs is not beneficial for facial nerve repair. PMID: 18627308 [PubMed - indexed for MEDLINE]
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Related Articles Aniridia: current pathology and management. Acta Ophthalmol. 2008 Nov;86(7):708-15 Authors: Lee H, Khan R, O'Keefe M Abstract Aniridia is a rare panocular disorder affecting the cornea, anterior chamber, iris, lens, retina, macula and optic nerve. It occurs because of mutations in PAX6 on band p13 of chromosome 11. It is associated with a number of syndromes, including Wilm's tumour, bilateral sporadic aniridia, genitourinary abnormalities and mental retardation (WAGR) syndrome. PAX6 mutations result in alterations in corneal cytokeratin expression, cell adhesion and glycoconjugate expression. This, in addition to stem-cell deficiency, results in a fragile cornea and aniridia-associated keratopathy (AAK). It also results in abnormalities in the differentiation of the angle, resulting in glaucoma. Glaucoma may also develop as a result of progressive angle closure from synechiae. There is cataract development, and this is associated with a fragile lens capsule. The iris is deficient. The optic nerve and fovea are hypoplastic, and the retina may be prone to detachment. Aniridia is a profibrotic disorder, and as a result many interventions--including penetrating keratoplasty and filtration surgery--fail. The Boston keratoprosthesis may provide a more effective approach in the management of AAK. Guarded filtration surgery appears to be effective in glaucoma. Despite our increasing understanding of the genetics and pathology of this condition, effective treatment remains elusive. PMID: 18937825 [PubMed - indexed for MEDLINE]
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Related Articles [Glaucoma neuroprotection--how far is it from a dream to reality]. Zhonghua Yan Ke Za Zhi. 2008 May;44(5):385-7 Authors: Ge J Abstract Although the drugs, such as Memantine, Calpain, Erythropoietin, have demonstrated exciting results for neuroprotection in laboratories, the phase III clinical trial of Memantine failed to prove such activity. So far, none of neuroprotection drugs has been approved by FDA for clinical use with the failure of Memantine clinical trail indicating that the gap between basic science research and clinical application in glaucomatous optic neuroprotection remains to be filled. This paper offers a new insight into the field of neuroprotection in glaucoma. To make the dream of optic neuroprotection to reality, we have to implement new perspective strategies to integrate technologies and findings from the researches of human genomics, proteomics, stem cells, and gene-transferred animal models. PMID: 18953889 [PubMed - indexed for MEDLINE]
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Related Articles Glaucoma alters the circadian timing system. PLoS One. 2008;3(12):e3931 Authors: Drouyer E, Dkhissi-Benyahya O, Chiquet C, WoldeMussie E, Ruiz G, Wheeler LA, Denis P, Cooper HM Abstract Glaucoma is a widespread ocular disease and major cause of blindness characterized by progressive, irreversible damage of the optic nerve. Although the degenerative loss of retinal ganglion cells (RGC) and visual deficits associated with glaucoma have been extensively studied, we hypothesize that glaucoma will also lead to alteration of the circadian timing system. Circadian and non-visual responses to light are mediated by a specialized subset of melanopsin expressing RGCs that provide photic input to mammalian endogenous clock in the suprachiasmatic nucleus (SCN). In order to explore the molecular, anatomical and functional consequences of glaucoma we used a rodent model of chronic ocular hypertension, a primary causal factor of the pathology. Quantitative analysis of retinal projections using sensitive anterograde tracing demonstrates a significant reduction (approximately 50-70%) of RGC axon terminals in all visual and non-visual structures and notably in the SCN. The capacity of glaucomatous rats to entrain to light was challenged by exposure to successive shifts of the light dark (LD) cycle associated with step-wise decreases in light intensity. Although glaucomatous rats are able to entrain their locomotor activity to the LD cycle at all light levels, they require more time to re-adjust to a shifted LD cycle and show significantly greater variability in activity onsets in comparison with normal rats. Quantitative PCR reveals the novel finding that melanopsin as well as rod and cone opsin mRNAs are significantly reduced in glaucomatous retinas. Our findings demonstrate that glaucoma impacts on all these aspects of the circadian timing system. In light of these results, the classical view of glaucoma as pathology unique to the visual system should be extended to include anatomical and functional alterations of the circadian timing system. PMID: 19079596 [PubMed - indexed for MEDLINE]
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Related Articles Effects of bone-marrow mesenchymal stem cells transplanted into vitreous cavity of rat injured by ischemia/reperfusion. Graefes Arch Clin Exp Ophthalmol. 2009 Apr;247(4):503-14 Authors: Li N, Li XR, Yuan JQ Abstract OBJECTIVE: To examine the survival, migration, integration, differentiation and the expression of various neurotrophic factors of bone-marrow mesenchymal stem cells (BMSCs) transplanted into the vitreous cavity of rats injured by ischemia/reperfusion(I/R). METHODS: The BMSCs were separated from rat marrow using the wall-sticking method, and cultured in vitro to expand. Flow cytometry detected the surface antigens of BMSCs. Ninety-six rats were randomly divided into four groups: normal control injected PBS(C+P), normal control injected BMSCs (C+B), ischemic/reperfusion injected PBS(I/R+P)and ischemic/reperfusion injected BMSCs(I/R+B). After retinal I/R injury was induced in each group by increasing intraocular pressure, 10 microl PBS and BMSC suspensions labeled by red fluorescence CM-Dil were immediately injected into the vitreous cavity. We observed the survival, migration and integration of BMSCs using confocal microscopy. The differentiation and expression of basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) of CM-Dil-labeled BMSCs were detected by immunofluorescent labeling and reserved by confocal microscopy. The expression of mRNA and proteins of bFGF, BDNF and CNTF were assayed by RT-PCR and Western Blot respectively. RESULTS: After transplantation to normal eyes, BMSCs labeled by CM-Dil were mostly present in the vitreous cavity, and did not migrate. After transplantation to I/R eyes, BMSCs labeled by CM-Dil were mostly present along with the inner limiting membrane. Only a few cells were integrated into the ganglion cell layer. Two or 4 weeks after transplantation, a few BMSCs labeled by CM-Dil were observed to express markers of neuron- neurone specific enolase (NSE), neurofilament (NF) and various neurotrophic factors. The BMSC-injected I/R model eyes showed less reduction in the number of RGCs than that of the I/R eyes with PBS injection. CONCLUSIONS: BMSC transplantation is a valuable neuroprotection tool for the treatment of retina and optic nerve diseases. PMID: 19084985 [PubMed - indexed for MEDLINE]
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Related Articles Low-dose busulphan conditioning and neonatal stem cell transplantation preserves vision and restores hematopoiesis in severe murine osteopetrosis. Exp Hematol. 2009 Feb;37(2):302-8 Authors: Askmyr M, Holmberg J, Flores C, Ehinger M, Hjalt T, Richter J Abstract OBJECTIVE: Infantile malignant osteopetrosis is a fatal disease caused by lack of functional osteoclasts. In most of patients, TCIRG1, encoding a subunit of a proton pump essential for bone resorption, is mutated. Osteopetrosis leads to bone marrow failure and blindness due to optic nerve compression. Oc/oc mice have a deletion in Tcirg1 and die around 3 to 4 weeks, but can be rescued by neonatal stem cell transplantation (SCT) after irradiation conditioning. However, as irradiation of neonatal mice results in retinal degeneration, we wanted to investigate whether conditioning with busulphan prior to SCT can lead to preservation of vision and reversal of osteopetrosis in the oc/oc mouse model. MATERIALS AND METHODS: Pregnant dams were conditioned with busulphan and their litters transplanted with 1 x 10(6) normal lineage-depleted bone marrow cells intravenously or intraperitoneally. Mice were followed in terms of survival and engraftment level, as well as with peripheral blood lineage analysis, bone and eye histopathology and a visual-tracking drum test to assess vision. RESULTS: Busulphan at 15 mg/kg was toxic to oc/oc mice. However, six of seven oc/oc mice conditioned with busulphan 7.5 mg/kg survived past the normal lifespan with 10% engraftment, correction of the skeletal phenotype, and normalization of peripheral blood lineages. Busulphan, in contrast to irradiation, did not have adverse effects on the retina as determined by histopathology, and 8 weeks after transplantation control and oc/oc mice retained their vision. CONCLUSION: Low-dose busulphan conditioning and neonatal SCT leads to prolonged survival of oc/oc mice, reverses osteopetrosis and prevents blindness even at low engraftment levels. PMID: 19100677 [PubMed - indexed for MEDLINE]
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Related Articles Retinal ganglion cell death and optic nerve degeneration by genetic ablation in adult mice. Exp Eye Res. 2009 Mar;88(3):542-52 Authors: Cho JH, Mu X, Wang SW, Klein WH Abstract Despite the magnitude of the problem, no effective treatments exist to prevent retinal ganglion cell (RGC) death and optic nerve degeneration from occurring in diseases affecting the human eye. Animal models currently available for developing treatment strategies suffer from cumbersome procedures required to induce RGC death or rely on mutations that induce defects in developing retinas rather than in mature retinas of adults. Our objective was to develop a robust genetically engineered adult mouse model for RGC loss and optic nerve degeneration based on genetic ablation. To achieve this, we took advantage of Pou4f2 (Brn3b), a gene activated immediately as RGCs begin to differentiate and expressed throughout life. We generated adult mice whose genomes harbored a conditional Pou4f2 allele containing a floxed-lacZ-stop-diphtheria toxin A cassette and a CAGG-Cre-ER transgene. In this bigenic model, Cre recombinase is fused to a modified estrogen nuclear receptor in which the estrogen-binding domain binds preferentially to the estrogen agonist tamoxifen rather than to endogenous estradiol. Upon binding to the estrogen-binding domain, tamoxifen derepresses Cre recombinase, leading to the efficient genomic deletion of the floxed-lacZ-stop DNA sequence and expression of diphtheria toxin A. Tamoxifen administered to adult mice at different ages by intraperitoneal injection led to rapid RGC loss, reactive gliosis, progressive degradation of the optic nerve over a period of several months, and visual impairment. Perhaps more reflective of human disease, partial loss of RGCs was achieved by modulating the tamoxifen treatment. Especially relevant for RGC death and optic nerve degeneration in human retinal pathologies, RGC-ablated retinas maintained their structural integrity, and other retinal neurons and their connections in the inner and outer plexiform layers appeared unaffected by RGC ablation. These events are hallmarks of progressive optic nerve degeneration observed in human retinal pathologies and demonstrate the validity of this model for use in developing stem cell therapies for replacing dead RGCs with healthy ones. PMID: 19109949 [PubMed - indexed for MEDLINE]
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Related Articles There is no evidence that . . . Arch Ophthalmol. 2009 Jan;127(1):94-6 Authors: Kushner BJ PMID: 19139347 [PubMed - indexed for MEDLINE]
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Related Articles Rat neurosphere cells protect axotomized rat retinal ganglion cells and facilitate their regeneration. J Neurotrauma. 2009 Jul;26(7):1147-56 Authors: Hill AJ, Zwart I, Samaranayake AN, Al-Allaf F, Girdlestone J, Mehmet H, Navarrete R, Navarrete C, Jen LS Abstract We investigated the ability of a population of rat neural stem and precursor cells derived from rat embryonic spinal cord to protect injured neurons in the rat central nervous system (CNS). The neonatal rat optic pathway was used as a model of CNS injury, whereby retinal ganglion cells (RGCs) were axotomized by lesion of the lateral geniculate nucleus one day after birth. Neural stem and precursor cells derived from expanded neurospheres (NS) were transplanted into the lesion site at the time of injury. Application of Fast Blue tracer dye to the lesion site demonstrated that significant numbers of RGCs survived at 4 and 8 weeks in animals that received a transplant, with an average of 28% survival, though in some individual cases survival was greater than 50%. No RGCs survived in animals that received a lesion alone. Furthermore, labeled RGCs were also observed when Fast Blue was applied to the superior colliculus (SC) at 4 weeks, suggesting that neurosphere cells also facilitated RGC to regenerate to their normal target. Transplanted cells did not migrate or express neural markers after transplantation, and secreted several neurotrophic factors in vitro. We conclude that NS cells can protect injured CNS neurons and promote their regeneration. These effects are not attributable to cell replacement, and may be mediated via secretion of neurotrophic factors. Thus, neuroprotection by stem cell populations may be a more viable approach for treatment of CNS disorders than cell replacement therapy. PMID: 19203229 [PubMed - indexed for MEDLINE]
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Related Articles Umbilical cord blood mesenchymal stromal cells are neuroprotective and promote regeneration in a rat optic tract model. Exp Neurol. 2009 Apr;216(2):439-48 Authors: Zwart I, Hill AJ, Al-Allaf F, Shah M, Girdlestone J, Sanusi AB, Mehmet H, Navarrete R, Navarrete C, Jen LS Abstract Exploitation of the ability of stem cells to protect damaged neuronal tissue may be a more viable strategy than cell replacement for repair of the central nervous system (CNS). In this study we assessed the capacity of human umbilical cord blood (hUCB)-derived mesenchymal stromal cells (MSCs) to protect and promote regeneration of axotomised neurons within the rat optic system. The optic tract of neonatal rats was transected at the level of the lateral geniculate nucleus, and MSCs were introduced into the lesion site. MSCs survived well up to 2 weeks after grafting, and did not migrate significantly or differentiate. In the presence of MSC grafts, host axonal processes were found to be present in the lesion site, and there was stimulation of an endogenous neural precursor population. Four weeks after grafting, retrograde tracer experiments demonstrated that grafted MSCs, as well as cells of a human fibroblast line, exerted a neuroprotective effect, rescuing a significant percentage of axotomised retinal ganglion cells (RGCs). Further experiments with retrograde and anterograde tracers strongly indicated that MSCs could also promote re-growth of axotomised RGCs to their target, the superior colliculus (SC). Further analysis showed that hUCB-derived MSCs secreted several immunomodulatory and neurotrophic factors in vitro, including TGFbeta1, CNTF, NT-3 and BDNF, which are likely to play a role in neuroprotection. Our data indicate that hUCB-derived MSCs may be an easily accessible, widely available source of cells that can contribute towards neural repair through rescue and regeneration of injured neurons. PMID: 19320003 [PubMed - indexed for MEDLINE]
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Related Articles Transplanted oligodendrocyte precursor cells reduce neurodegeneration in a model of glaucoma. Invest Ophthalmol Vis Sci. 2009 Sep;50(9):4244-53 Authors: Bull ND, Irvine KA, Franklin RJ, Martin KR Abstract PURPOSE: Glaucoma is a common neurodegenerative disease for which current therapies are often insufficient; thus, new neuroprotective strategies are an important goal. Stem cells are attracting increasing attention as mediators of neuroprotection, often conferred via the trophic support of injured neurons. The purpose of our investigation was to determine whether oligodendrocyte precursor cells (OPCs), a type of neural stem cell, can protect retinal ganglion cells (RGCs) from glaucomatous damage in vivo. METHODS: Intraocular pressure was chronically increased by trabecular laser treatment delivered unilaterally to adult rat eyes. OPCs were isolated in vitro and then transplanted intravitreally either before, or concurrent with, injury induction. Survival, migration, differentiation, and integration of grafted cells were assessed by immunohistochemistry. RGC survival was assessed by optic nerve axon quantification. RESULTS: Transplanted OPCs were found to survive within the eye for at least 12 weeks and to localize close to the RGCs. Moreover, OPCs significantly enhanced the survival of RGCs in the glaucomatous eye, but only when concomitantly activated by inflammation. Axonal loss relative to the untreated fellow eye was 28.34% +/- 11.51% in eyes that received activated OPCs, compared with 60.34% +/- 8.28% in control eyes (mean +/- SEM; P = 0.05). Amelioration of RGC death was not attributable to inflammation but relied on an interaction between inflammatory cells and OPCs. Engrafted cells also displayed multipotentiality in vivo. CONCLUSIONS: The impressive neuroprotection conferred by OPCs in this model suggests stem cell-based therapies should be explored further as a potential treatment for glaucoma. PMID: 19357352 [PubMed - indexed for MEDLINE]
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Related Articles Ethmoiditis-associated apex syndrome may result in temporary blindness after allo-SCT. Bone Marrow Transplant. 2009 Dec;44(12):825-6 Authors: Olsson R, Juto JE, Mattsson J PMID: 19421176 [PubMed - indexed for MEDLINE]
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Related Articles Both systemic and local application of granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy. BMC Neurosci. 2009;10:49 Authors: Frank T, Schlachetzki JC, Göricke B, Meuer K, Rohde G, Dietz GP, Bähr M, Schneider A, Weishaupt JH Abstract BACKGROUND: The hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF) plays a crucial role in controlling the number of neutrophil progenitor cells. Its function is mediated via the G-CSF receptor, which was recently found to be expressed also in the central nervous system. In addition, G-CSF provided neuroprotection in models of neuronal cell death. Here we used the retinal ganglion cell (RGC) axotomy model to compare effects of local and systemic application of neuroprotective molecules. RESULTS: We found that the G-CSF receptor is robustly expressed by RGCs in vivo and in vitro. We thus evaluated G-CSF as a neuroprotectant for RGCs and found a dose-dependent neuroprotective effect of G-CSF on axotomized RGCs when given subcutaneously. As stem stell mobilization had previously been discussed as a possible contributor to the neuroprotective effects of G-CSF, we compared the local treatment of RGCs by injection of G-CSF into the vitreous body with systemic delivery by subcutaneous application. Both routes of application reduced retinal ganglion cell death to a comparable extent. Moreover, G-CSF enhanced the survival of immunopurified RGCs in vitro. CONCLUSION: We thus show that G-CSF neuroprotection is at least partially independent of potential systemic effects and provide further evidence that the clinically applicable G-CSF could become a treatment option for both neurodegenerative diseases and glaucoma. PMID: 19442279 [PubMed - indexed for MEDLINE]
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Related Articles A case of autoimmune-related retinopathy and optic neuropathy syndrome treated by autologous nonmyeloablative hematopoietic stem cell transplantation. J Neuroophthalmol. 2009 Mar;29(1):43-9 Authors: Oyama Y, Burt RK, Thirkill C, Hanna E, Merrill K, Keltner J Abstract Autoimmune-related retinopathy and optic neuropathy (ARRON) syndrome is characterized by visual loss and often the presence of antibodies against retinal or optic nerve antigens in the absence of cancer. Limited success has been reported in treatment of ARRON syndrome with medications that suppress the immune system. In many patients, current strategies are insufficient to control the disease. A 47-year-old woman with progressive visual and hearing loss attributed to ARRON syndrome that was resistant to conventional therapies underwent autologous hematopoietic stem cell transplantation (HSCT). Clinical manifestations appeared to stabilize. This report suggests that autologous HSCT may have a therapeutic role in ARRON syndrome. PMID: 19458576 [PubMed - indexed for MEDLINE]
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Related Articles Cancer stem cells in pediatric brain tumors. Curr Stem Cell Res Ther. 2009 Dec;4(4):298-305 Authors: Lasky JL, Choe M, Nakano I Abstract Central nervous system (CNS) tumors remain the leading cause of death among pediatric neoplasms. Although standard therapies cure many pediatric CNS tumors, the long-term cognitive and physical consequences of these therapies are devastating. Furthermore, recurrent disease carries a dismal prognosis. Although recent studies have focused on molecular mechanisms that underlie the initiation and progression of adult glioblastoma multiforme (GBM), these tumors differ phenotypically and at a molecular level from pediatric brain tumors. Recent investigations have identified a stem cell population, termed "brain tumor stem cells" (BTSC) within the heterogeneous cell populations that comprise malignant brain tumors which may be partly responsible for the resistance to current therapies. These have been identified in several pediatric tumors including medulloblastoma, ependymomas, and malignant gliomas. By exploiting molecular differences present within these heterogeneous populations of brain tumor cells, we may be able to achieve specific eradication of BTSC and long-lasting remissions, while causing less toxicity to normal tissues. In this review, we describe the issues surrounding the identification and characterization of BTSC, the molecular biology of BTSC for different pediatric brain tumors, and suggest future avenues for the development of treatments for this devastating disease. PMID: 19500067 [PubMed - indexed for MEDLINE]
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Related Articles Mutation of OPA1 gene causes deafness by affecting function of auditory nerve terminals. Brain Res. 2009 Dec 1;1300:97-104 Authors: Huang T, Santarelli R, Starr A Abstract Autosomal dominant optic atrophy (DOA) is a retinal neuronal degenerative disease characterized by a progressive bilateral visual loss. We report on two affected members of a family with dominantly inherited neuropathy of both optic and auditory nerves expressed by impaired visual acuity, moderate pure tone hearing loss, and marked loss of speech perception. We investigated cochlear abnormalities accompanying the hearing loss and the effects of cochlear implantation. We sequenced OPA1 gene and recorded cochlear receptor and neural potentials before cochlear implantation. Genetic analysis identified R445H mutation in OPA1 gene. Audiological studies showed preserved cochlear receptor outer hair cell activities (otoacoustic emissions) and absent or abnormally delayed auditory brainstem responses (ABRs). Trans-tympanic electrocochleography (ECochG) showed prolonged low amplitude negative potentials without auditory nerve compound action potentials. The latency of onset of the cochlear potentials was within the normal range found for inner hair cell summating receptor potentials. The duration of the negative potential was reduced to normal during rapid stimulation consistent with adaptation of neural sources generating prolonged cochlear potentials. Both subjects had cochlear implants placed with restoration of hearing thresholds, speech perception, and synchronous activity in auditory brainstem pathways. The results suggest that deafness accompanying this OPA1 mutation is due to altered function of terminal unmyelinated portions of auditory nerve. Electrical stimulation of the cochlea activated proximal myelinated portions of auditory nerve to restore hearing. PMID: 19733158 [PubMed - indexed for MEDLINE]
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Related Articles Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Invest Ophthalmol Vis Sci. 2010 Apr;51(4):2051-9 Authors: Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI, Martin KR Abstract Purpose. Retrograde neurotrophic factor transport blockade has been implicated in the pathophysiology of glaucoma. Stem cell transplantation appears to ameliorate some neurodegenerative conditions in the brain and spinal cord, in part by neurotrophic factor secretion. The present study was conducted to determine whether local or systemic bone marrow-derived mesenchymal stem cell (MSC) transplantation can confer neuroprotection in a rat model of laser-induced ocular hypertensive glaucoma. Methods. MSCs were isolated from the bone marrow of adult wild-type and transgenic rats that ubiquitously express green fluorescent protein. MSCs were transplanted intravitreally 1 week before, or intravenously on the day of, ocular hypertension induction by laser photocoagulation of the trabecular meshwork. Ocular MSC localization and integration were determined by immunohistochemistry. Optic nerve damage was quantified by counting axons within optic nerve cross-sections 4 weeks after laser treatment. Results. After intravitreal transplantation, MSCs survived for at least 5 weeks. Cells were found mainly in the vitreous cavity, though a small proportion of discrete cells migrated into the host retina. Intravitreal MSC transplantation resulted in a statistically significant increase in overall RGC axon survival and a significant decrease in the rate of RGC axon loss normalized to cumulative intraocular pressure exposure. After intravenous transplantation, MSCs did not migrate to the injured eye. Intravenous transplantation had no effect on optic nerve damage. Conclusions. Local, but not systemic, transplantation of MSCs was neuroprotective in a rat glaucoma model. Autologous intravitreal transplantation of MSCs should be investigated further as a potential neuroprotective therapy for glaucoma. PMID: 19933193 [PubMed - indexed for MEDLINE]
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Related Articles Blindness in neurological disease: a short overview of new therapies from translational research. Curr Opin Neurol. 2010 Feb;23(1):1-3 Authors: Acheson J PMID: 20038826 [PubMed - indexed for MEDLINE]
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Related Articles Visual field results and optic disc morphology in patients treated with allogeneic stem-cell transplantation in childhood. Acta Ophthalmol. 2011 Feb;89(1):62-9 Authors: Törnquist AL, Olsson M, Martin L, Winiarski J, Fahnehjelm KT Abstract PURPOSE: This study aimed to describe the Rarebit (RB) visual field and optic nerve size/morphology in patients treated with allogeneic stem-cell transplantation (SCT) in childhood, and to determine the impact of ocular status and conditioning regimens such as total body irradiation (TBI), chemotherapy and/or immunosuppressive drugs on the RB visual field. METHODS: Ocular fundi were evaluated in 79 patients. Digital analyses regarding optic disc area (DA), rim area (RA) and cup area (CA) were performed in 45 of 49 patients. RB visual field testing was performed in 53 of 79 patients. The mean hit rate (MHR) was compared to corneal status, cataract, diagnosis and pre and post-SCT treatment. Two groups of healthy children and young adults (RB = 51, disc analysis = 49) were used as controls. RESULTS: The SCT patients, examined at a median age of 15.4 years, had a significantly lower MHR [median 91% (range 45-99) right eye and 91% (range 41-91) left eye] compared to controls [median 96% (range 78-100) right eye]. SCT patients treated surgically for cataract and with intraocular lenses (IOLs) had a significantly lower MHR compared to other SCT patients. The MHR was also significantly influenced by type of conditioning. Patients conditioned with chemotherapy other than busulfan had significantly better MHR compared to those who had received single-dose TBI. SCT patients had a significantly larger CA and smaller RA than the controls. CONCLUSION: Patients treated with SCT in childhood have a significantly lower MHR than controls when examined with RB. Also, patients surgically treated for cataract and with IOL implantation had a significantly lower MHR. PMID: 20064124 [PubMed - indexed for MEDLINE]
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Related Articles Strategies for optic nerve rescue and regeneration in glaucoma and other optic neuropathies. Drug Discov Today. 2010 Apr;15(7-8):287-99 Authors: Dahlmann-Noor AH, Vijay S, Limb GA, Khaw PT Abstract Glaucoma is the most common age-related optic nerve disease and also the most common neuropathy, affecting approximately 60 million people worldwide in its most common forms. This figure is expected to rise to 80 million by 2020. Glaucoma is a neurodegenerative disease in which various triggers induce cascades of secondary events, which ultimately lead to apoptotic retinal ganglion cell (RGC) death. The main risk factor for glaucomatous nerve damage is raised pressure in the eye. Understanding the cascades mediating optic nerve damage enables the development of new, neuroprotective treatment strategies that might not only target the initial insult but also prevent or delay secondary neurodegeneration. Furthermore, neuroregeneration and repopulation of the visual pathway by stem or neural precursor cells is becoming possible. Increasing understanding of the pathways involved in directed axon growth and manipulation of stem and progenitor cells towards an RGC fate have facilitated first successes in animal models of glaucoma. PMID: 20197108 [PubMed - indexed for MEDLINE]
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Related Articles Rapid vision loss associated with fludarabine administration. Retina. 2010 Sep;30(8):1272-7 Authors: Bishop RJ, Ding X, Heller CK, Illei G, Caruso R, Cunningham D, Pavletic S, Chan CC Abstract PURPOSE: The purpose of this study was to report the clinical and pathologic findings of three cases of rapid vision loss associated with fludarabine toxicity. METHODS: A retrospective, single-center case series was conducted. Autopsies of the eyes from three cases were performed. RESULTS: A 23-year-old man (Case 1) with systemic lupus erythematosus developed rapid and severe vision loss, generalized neurologic decline, and eventual death after administration of fludarabine before stem cell transplantation. A 48-year-old woman (Case 2) and a 60-year-old man (Case 3), both with metastatic melanoma, had similar courses after receiving fludarabine as part of a preparatory regimen before adoptive cell therapy. Fundus examination showed punctuate yellow flecks in the macula after visual decline in two cases. In all three cases, serum antiretinal antibodies were negative before and after treatment; electrophysiological testing showed markedly decreased B-waves; and pathologic analysis showed loss of retinal bipolar and ganglion cells, gliosis within the retina and optic nerve, and optic nerve atrophy. CONCLUSION: Fludarabine toxicity can result in severe vision loss attributable to damage to retinal bipolar and ganglion cells. Although effective treatments are not known, care should be taken to consider fludarabine toxicity in patients who present with vision loss approximately 1 month after treatment. PMID: 20224467 [PubMed - indexed for MEDLINE]
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Related Articles Death of axotomized retinal ganglion cells delayed after intraoptic nerve transplantation of olfactory ensheathing cells in adult rats. Cell Transplant. 2010;19(2):159-66 Authors: Wu MM, Fan DG, Tadmori I, Yang H, Furman M, Jiao XY, Young W, Sun D, You SW Abstract Intraorbital transection of the optic nerve (ON) always induces ultimate apoptosis of retinal ganglion cells (RGCs) and consequently irreversible defects of vision function. It was demonstrated that transplanted olfactory ensheathing cells (OECs) in partially injured spinal cord have a distant in vivo neuroprotective effect on descending cortical and brain stem neurons. However, this study gave no answers to the question whether OECs can protect the central sensitive neurons with a closer axonal injury because different neurons respond variously to similar axonal injury and the distance between the neuronal soma and axonal injury site has a definite effect on the severity of neuronal response and apoptosis. In the present study, we investigated the effect of transplanted OECs on RGCs after intraorbital ON transection in adult rats. Green fluorescent protein (GFP)-OECs were injected into the ocular stumps of transected ON and a significantly higher number of surviving RGCs was found together with a consistent marked increase in the mRNA and protein levels of BDNF in the ON stump and retina in the OEC-treated group at 7 days, but not 2 and 14 days, time point when compared to the control group. Our findings suggest that OEC transplantation induces the expression of BDNF in the ocular ON stump and retina and delays the death of axotomized RGCs at a certain survival period. PMID: 20350358 [PubMed - indexed for MEDLINE]
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Related Articles Mucopolysaccharidosis VI. Orphanet J Rare Dis. 2010;5:5 Authors: Valayannopoulos V, Nicely H, Harmatz P, Turbeville S Abstract Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 microg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 microg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided. PMID: 20385007 [PubMed - indexed for MEDLINE]
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Related Articles Results of a prospective study for the treatment of unilateral retinoblastoma. Pediatr Blood Cancer. 2010 Jul 15;55(1):60-6 Authors: Chantada GL, Fandiño AC, Guitter MR, Raslawski EC, Dominguez JL, Manzitti J, de Dávila MT, Zubizarreta P, Scopinaro M Abstract BACKGROUND: Few prospective studies about the management of unilateral retinoblastoma with pathology risk factors (PRFs) have been published. METHODS: Patients (n = 114) were divided into four groups: Group 1 (initial chemoreduction) (n = 17). Groups 2 and 3, included patients initially enucleated with no, or lower risk PRFs: (n = 65) and with higher risk PRFs (n = 30), respectively. The later included postlaminar optic nerve involvement (PLONI) (n = 23), tumor at resection margin of optic nerve (n = 5) or isolated scleral invasion (n = 2). Group 3 received adjuvant chemotherapy including a total eight cycles of carboplatin and etoposide, alternating with cyclophosphamide, idarubicin, and vincristine. Orbital radiotherapy (45 Gy) was given to patients with invasion to the resection margin. Group 4 included patients with metastatic disease (n = 2). They were given neoadjuvant therapy followed by surgery and high-dose chemotherapy and autologous stem cell rescue. RESULTS: Five-year event-free survival is 0.94 (1 for Group 1, 0.94 for Group 2, 0.96 for Group 3, and 0 for Group 4). Events included. Group 2: Systemic relapse (n = 2) and combined orbital and CNS relapse (n = 1). Relapsing patients had PLONI (n = 2) and isolated focal choroidal invasion (n = 1). Group 3: CNS relapse (n = 1) in a patient with tumor at the resection margin of optic nerve. Group 4: CNS relapse (n = 2). Only one relapsed patient survived. Eight of 17 eyes treated conservatively were preserved. CONCLUSIONS: The survival of patients with unilateral retinoblastoma was excellent and 60% were spared from adjuvant treatment. Our intensive regimen was likely to be effective for prevention of metastasis in patients with higher risk PRFs. PMID: 20486172 [PubMed - indexed for MEDLINE]
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Related Articles High-dose chemotherapy with autologous hematopoietic stem cell rescue for stage 4B retinoblastoma. Pediatr Blood Cancer. 2010 Jul 15;55(1):149-52 Authors: Dunkel IJ, Chan HS, Jubran R, Chantada GL, Goldman S, Chintagumpala M, Khakoo Y, Abramson DH Abstract BACKGROUND: Stage 4b retinoblastoma (central nervous system metastatic disease) has been lethal in virtually all cases reported. Here we describe a series of eight patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy with autologous hematopoietic stem cell rescue. PROCEDURE: Induction chemotherapy included cyclophosphamide and/or carboplatin with a topoisomerase inhibitor. High-dose chemotherapy regimens were carboplatin and thiotepa with or without etoposide (n = 3) or carboplatin, etoposide, and cyclophosphamide (n = 2). RESULTS: Seven patients had leptomeningeal disease and one patient had only direct extension to the CNS via the optic nerve. Three patients had stage 4b disease at the time of original diagnosis of the intra-ocular retinoblastoma; five had later onset at a median of 12 months (range 3-69 months). One patient died of toxicity (septicemia and multi-organ system failure) during induction and two had disease progression prior to high-dose chemotherapy. Five patients received high-dose chemotherapy at a median of 6 months (range 4-6) post-diagnosis of stage 4b disease. Two patients survive event-free at 40 and 101 months; one was irradiated following recovery from the high-dose chemotherapy. CONCLUSIONS: Intensive multimodality therapy may be beneficial for some patients with stage 4b retinoblastoma. Longer follow-up will determine whether it has been curative. PMID: 20486181 [PubMed - indexed for MEDLINE]
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Related Articles Malignant transformation of a medulloepithelioma of the optic nerve. Orbit. 2010 Jun;29(3):161-4 Authors: Lindegaard J, Heegaard S, Toft PB, Nysom K, Prause JU Abstract OBJECTIVE: To describe a case of malignant transformation of a medulloepithelioma of the optic nerve. METHODS: A 3-year-old boy presented with right-sided proptosis, swollen eyelids, restricted ocular movements, pain and nausea. Visual acuity was hand motions. A benign non-teratoid medulloepithelioma of the optic nerve was surgically removed. Due to relapse in the orbit 10 months postoperatively enucleation and partial orbital exenteration were performed. Light microscopy and immunohistochemistry now revealed a malignant medulloepithelioma. The boy was further treated with chemotherapy and radiotherapy and is still alive 36 months after primary surgery. RESULTS: Medulloepithelioma of the optic nerve is extremely rare. Only eight cases have been described in the literature. Unlike intraocular medulloepithelioma, all have been malignant tumours. This is the first case described of a benign medulloepithelioma of the optic nerve, later transforming into a malignant tumour. One third of patients with medulloepithelioma of the optic nerve have died from direct intracranial spread or metastasis to the central nervous system (CNS). CONCLUSIONS: Medulloepithelioma of the optic nerve should be considered malignant despite morphology with tendency to spread to the CNS. Furthermore; it should be considered as a differential diagnosis when observing a tumour of the optic nerve in a child. PMID: 20497085 [PubMed - indexed for MEDLINE]
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Related Articles Orbital involvement in Bing-Neel syndrome. J Neuroophthalmol. 2010 Sep;30(3):255-9 Authors: Stacy RC, Jakobiec FA, Hochberg FH, Hochberg EP, Cestari DM Abstract Bing-Neel syndrome (BNS) is defined as intracranial involvement of Waldenström macroglobulinemia (WM). Few cases of orbital involvement have been reported. A 51-year-old man with a history of WM developed bilateral orbitopathy and optic neuropathy. Orbital biopsy, cerebrospinal fluid studies, and neuroimaging confirmed the diagnosis of BNS involving the orbital soft tissues, optic nerves, meninges, and cauda equina. The neuro-ophthalmic manifestations resolved after parenteral and intrathecal chemotherapy in addition to autologous stem cell transplantation. The rare neuro-ophthalmic manifestations of BNS may require a multifaceted approach to therapy. PMID: 20548243 [PubMed - indexed for MEDLINE]
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Related Articles Current approaches and future prospects for stem cell rescue and regeneration of the retina and optic nerve. Can J Ophthalmol. 2010 Aug;45(4):333-41 Authors: Dahlmann-Noor A, Vijay S, Jayaram H, Limb A, Khaw PT Abstract The 3 most common causes of visual impairment and legal blindness in developed countries (age-related macular degeneration, glaucoma, and diabetic retinopathy) share 1 end point: the loss of neural cells of the eye. Although recent treatment advances can slow down the progression of these conditions, many individuals still suffer irreversible loss of vision. Research is aimed at developing new treatment strategies to rescue damaged photoreceptors and retinal ganglion cells (RGC) and to replace lost cells by transplant. The neuroprotective and regenerative potential of stem and progenitor cells from a variety of sources has been explored in models of retinal disease and ganglion cell loss. Continuous intraocular delivery of neurotrophic factors via stem cells (SC) slows down photoreceptor cells and RGC loss in experimental models. Following intraocular transplantation, SC are capable of expressing proteins and of developing a morphology characteristic of photoreceptors or RGC. Recently, recovery of vision has been achieved for the first time in a rodent model of retinal dystrophy, using embryonic SC differentiated into photoreceptors prior to transplant. This indicates that clinically significant synapse formation and acquisition of the functional properties of retinal neurons, and restoration of vision, are distinct future possibilities. PMID: 20648090 [PubMed - indexed for MEDLINE]
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Related Articles Diagnosis and management of ophthalmological features in patients with mucopolysaccharidosis. Br J Ophthalmol. 2011 May;95(5):613-9 Authors: Ferrari S, Ponzin D, Ashworth JL, Fahnehjelm KT, Summers CG, Harmatz PR, Scarpa M Abstract Ocular pathology is common in patients with mucopolysaccharidosis (MPS), a hereditary lysosomal storage disorder, where the eye as well as other tissues accumulate excessive amounts of glycosaminoglycans. Despite genetic and phenotypic heterogeneity within and between different types of MPS, the disease symptoms and clinical signs often manifest during the first 6 months of life with increasing head size, recurrent infections, umbilical hernia, growth retardation and skeletal problems. Typical ocular features include corneal clouding, ocular hypertension/glaucoma, retinal degeneration and optic nerve atrophy. Visual deterioration and sensitivity to light may substantially reduce the quality of life in MPS patients, particularly when left untreated. As an early intervention, haematopoietic stem cell transplantation and/or enzyme replacement therapy are likely to improve patients' symptoms and survival, as well as visual outcome. Thus, it is of utmost importance to ensure proper detection and accurate diagnosis of MPS at an early age. It is of fundamental value to increase awareness and knowledge among ophthalmologists of the ocular problems affecting MPS patients and to highlight potential diagnostic pitfalls and difficulties in patient care. This review provides insight into the prevalence and severity of ocular features in patients with MPS and gives guidance for early diagnosis and follow-up of MPS patients. MPS poses therapeutic challenges in ocular management, which places ophthalmologists next to paediatricians at the forefront of interventions to prevent long-term sequelae of this rare but serious disease. PMID: 20852315 [PubMed - indexed for MEDLINE]
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Related Articles Intravitreal injections of neurotrophic factors secreting mesenchymal stem cells are neuroprotective in rat eyes following optic nerve transection. Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6394-400 Authors: Levkovitch-Verbin H, Sadan O, Vander S, Rosner M, Barhum Y, Melamed E, Offen D, Melamed S Abstract PURPOSE: To evaluate the neuroprotective effect of intravitreal injections of neurotrophic factors secreting mesenchymal stem cells (NTF-SCs) on the survival of retinal ganglion cells (RGCs) in rat eyes after optic nerve transection (ONT). METHODS: Rat and human bone marrow-derived mesenchymal stem cells (MSCs) were induced to secrete high levels of NTF. The neuroprotective effect from intravitreally injected untreated MSCs or NTF-SCs was compared with that from PBS injections using an ONT model in 146 rats. RGCs were labeled by applying rhodamine dextran to the orbital optic nerve or by injecting Fluorogold into the superior colliculus. Cell- and saline-treated eyes were compared 8 days after ONT. For tracking, MSCs and NTF-SCs were labeled with PKH26 and analyzed at 2 hours and at 10, 17, and 24 days using immunohistochemistry and RT-PCR. RESULTS: Mean RGC survival at 8 days after transection increased significantly after intravitreal injections of human NTF-SCs (69% ± 3%) or of untreated human MSCs (66% ± 5%) versus PBS (46% ± 3%; P = 0.0005 and P = 0.03, respectively). In an additional set of experiments, human NTF-SCs versus PBS were significantly neuroprotective, but bone marrow-derived rat NTF-SCs were not (P = 0.001 and P = 0.1, respectively). Immunohistochemistry demonstrated that human-derived MSCs, human NTF-SCs, and rat-derived NTF-SCs survived at least 24 days after intravitreal injection. CONCLUSIONS: Bone marrow-derived MSCs can deliver NTFs by intravitreal injection and can be neuroprotective after ONT. This approach might be further studied to deliver NTFs by autotransplantation in glaucomatous eyes. PMID: 20926814 [PubMed - indexed for MEDLINE]
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Related Articles Future possibilities in glaucoma therapy. Med Sci Monit. 2010 Nov;16(11):RA252-9 Authors: Wierzbowska J, Robaszkiewicz J, Figurska M, Stankiewicz A Abstract Glaucoma is a group of eye diseases causing irreversible optic nerve damage. This review presents 4 elements of future glaucoma treatment strategies: baroprotection, vasoprotection, neuroprotection and gene therapy. New baroprotection includes compounds that alter the actin cytoskeleton (rho-kinase inhibitors, latrunculin, cytochalasin), new drugs that enhance aqueous outflow via the trabecular meshwork (statins, steroid antagonists) and via the uveoscleral route (EP2 agonists, 5-HT2 agonists), as well as new classes of components that suppress aqueous humor formation (cannabinoids). Vasoprotection includes blocking reperfusion injury (NOS-2 inhibitors, endothelin blockers, MMP-9 inhibitors). Concerning neuroprotection antiamyloids antibodies, erythropoietin and caspase inhibitors are discussed. Gene therapy may target various effectors: the trabecular meshwork (cytoskeleton regulatory proteins, miocyllin, MMPs), the ciliary body epithelium (genes modifying aqueous humor production, neuropeptides), the ciliary body cells (MMPs, genes of local PGs biosynthesis, ciliary muscle relaxants), the retinal ganglion cells (neurotrophin genes, anti-apoptotic genes), Müller cells (neurotrophins, GLAST) and conjunctiva (gene of chloramphenicol acetyltransferase, inhibitor p21). Experimental studies on the graft mesenchymal stem cells and mature retinal cells to replace the dead retinal ganglion cells are advanced. Immunotherapy, offering a vaccination, providing protection against loss of retinal ganglion cells, has been investigated. PMID: 20980972 [PubMed - indexed for MEDLINE]
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Related Articles Investigating regeneration and functional integration of CNS neurons: lessons from zebrafish genetics and other fish species. Biochim Biophys Acta. 2011 Mar;1812(3):364-80 Authors: Fleisch VC, Fraser B, Allison WT Abstract Zebrafish possess a robust, innate CNS regenerative ability. Combined with their genetic tractability and vertebrate CNS architecture, this ability makes zebrafish an attractive model to gain requisite knowledge for clinical CNS regeneration. In treatment of neurological disorders, one can envisage replacing lost neurons through stem cell therapy or through activation of latent stem cells in the CNS. Here we review the evidence that radial glia are a major source of CNS stem cells in zebrafish and thus activation of radial glia is an attractive therapeutic target. We discuss the regenerative potential and the molecular mechanisms thereof, in the zebrafish spinal cord, retina, optic nerve and higher brain centres. We evaluate various cell ablation paradigms developed to induce regeneration, with particular emphasis on the need for (high throughput) indicators that neuronal regeneration has restored sensory or motor function. We also examine the potential confound that regeneration imposes as the community develops zebrafish models of neurodegeneration. We conclude that zebrafish combine several characters that make them a potent resource for testing hypotheses and discovering therapeutic targets in functional CNS regeneration. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases. PMID: 21044883 [PubMed - indexed for MEDLINE]
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Related Articles [Present status on studies of differentiation into retinal neurons and pigmented cell from induced pluripotent stem cells]. Zhonghua Yan Ke Za Zhi. 2010 Dec;46(12):1139-42 Authors: Meng FX, Guo WY Abstract Somatic cells could be induced into pluripotent stem (iPS) cells through transferring special genes (Oct4, Sox2, c-myc and Klf4). This has brought a revolutionary change in stem cell study and application. The generation of iPS cells has great potential and enormous significance as it can resolve some insurmountable problems in stem cells research, such as ethical dilemma, immune rejection, etc. Because of these characteristics, it plays an important role in the repair of various tissues and organs. Rapid progress in this field during the past 3 years convinced us that iPS cells will be more and more applicable in tissue engineering. The present paper reviews the progress of pre-clinical study on iPS cells in the treatment of retinal and optic nerve diseases. PMID: 21211229 [PubMed - indexed for MEDLINE]
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Related Articles Corneal hysteresis in mucopolysaccharidosis I and VI. Acta Ophthalmol. 2012 Aug;90(5):445-8 Authors: Fahnehjelm KT, Chen E, Winiarski J Abstract PURPOSE: High intraocular pressure (IOP) and glaucoma are often suspected in patients with mucopolysaccharidosis (MPS). To determine corneal hysteresis (CH) and IOP in children with mucopolysaccharidosis I-Hurler (MPS I-H) and MPS VI. METHODS: Clinical measurements with ocular response analyzer (ORA). RESULTS: In seven patients, five with MPS I-H treated with stem cell transplantation (SCT), and two with MPS VI, one treated with SCT and the other with enzyme therapy, the IOP was examined with ORA. Ocular response analyzer measurements were made at a median age of 8.7 years in the patients with MPS I-H and at a median age of 9.3 years in the patients with MPS VI. Earlier measurements had raised suspicion of high IOP in one patient. The ORA showed an increased CH and a falsely high IOP values in all 14 eyes. The recalculated IOPs were normal in all 14 eyes. Mild to severe corneal opacities were present in all 14 eyes. Optic disc areas, borders and cupping were clinically normal in the 12 of 14 eyes that were possible to examine. Severe corneal opacities hampered optic disc evaluation in the older patient with MPS VI. Three eyes in two patients had normal thickness of the retinal nerve fibre layer measured with scanning laser polarimetry with corneal compensation (GDx VCC). No patient was diagnosed or treated for glaucoma. CONCLUSION: The IOPs are often falsely high because of an increased resistance of the cornea and correlate to the extent of corneal clouding. In this small, cross-sectional study, it appears that corneal resistance is directly correlated with corneal clouding, although a longitudinal study that evaluates resistance as the cornea clears with treatment would provide more direct evidence that corneal deposits are directly related to resistance. A correct measured IOP can avoid unnecessary medical or surgical hypotensive treatment. PMID: 21232085 [PubMed - indexed for MEDLINE]
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Related Articles Neuroprotection in glaucoma: recent and future directions. Curr Opin Ophthalmol. 2011 Mar;22(2):78-86 Authors: Danesh-Meyer HV Abstract PURPOSE OF REVIEW: The concept of neuroprotective therapy for glaucoma is that damage to retinal ganglion cells (RGCs) may be prevented by intervening in neuronal death pathways. This review focuses on strategies for neuroprotection and summarizes preclinical studies that have investigated potential agents over the last 2 years. RECENT FINDINGS: Part of the challenge of studies in neuroprotection has been the utilization of an animal model that resembles human glaucoma. Several models have been utilized including acute and chronic intraocular pressure elevation, the DBA/2J mouse, optic nerve axotomy and crush. NMDA inhibitors continued to be explored however with limited success in human trials. Memantine failed to demonstrate neuroprotection in phase III clinical trials. Although its mechanism of neuroprotection has not been fully elaborated, topical brimonidine has shown some neuroprotective benefits. Exogeneous neurotrophins delay, but do not prevent, RGC death. Bioenergetic neuroprotection that is enhancing the energy supply to RGC has been explored with benefits in animal models. Other strategies include TNF-α, modulation of the immune system and inflammation, and blocking apoptotic signals and stem cells. SUMMARY: Animal models of glaucoma and neuroprotective strategies continue to be refined. Establishing consensus guidelines for the execution and design of translational research in neuroprotection may optimize the facilitation of neuroprotection research. PMID: 21252670 [PubMed - indexed for MEDLINE]
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Related Articles Use of an adult rat retinal explant model for screening of potential retinal ganglion cell neuroprotective therapies. Invest Ophthalmol Vis Sci. 2011 May;52(6):3309-20 Authors: Bull ND, Johnson TV, Welsapar G, DeKorver NW, Tomarev SI, Martin KR Abstract PURPOSE. To validate an established adult organotypic retinal explant culture system for use as an efficient medium-throughput screening tool to investigate novel retinal ganglion cell (RGC) neuroprotective therapies. METHODS. Optimal culture conditions for detecting RGC neuroprotection in rat retinal explants were identified. Retinal explants were treated with various recognized, or purported, neuroprotective agents and cultured for either 4 or 7 days ex vivo. The number of cells surviving in the RGC layer (RGCL) was quantified using histologic and immunohistochemical techniques, and statistical analyses were applied to detect neuroprotective effects. RESULTS. The ability to replicate previously reported in vivo RGC neuroprotection in retinal explants was verified by demonstrating that caspase inhibition, brain-derived neurotrophic factor treatment, and stem cell transplantation all reduced RGCL cell loss in this model. Further screening of potential neuroprotective pharmacologic agents demonstrated that betaxolol, losartan, tafluprost, and simvastatin all alleviated RGCL cell loss in retinal explants, supporting previous reports. However, treatment with brimonidine did not protect RGCL neurons from death in retinal explant cultures. Explants cultured for 4 days ex vivo proved most sensitive for detecting neuroprotection. CONCLUSIONS. The current adult rat retinal explant culture model offers advantages over other models for screening potential neuroprotective drugs, including maintenance of neurons in situ, control of environmental conditions, and dissociation from other factors such as intraocular pressure. Verification that neuroprotection by previously identified RGC-protective therapies could be replicated in adult retinal explant cultures suggests that this model could be used for efficient medium-throughput screening of novel neuroprotective therapies for retinal neurodegenerative disease. PMID: 21345987 [PubMed - indexed for MEDLINE]
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Related Articles Protective effects of human umbilical cord blood stem cell intravitreal transplantation against optic nerve injury in rats. Graefes Arch Clin Exp Ophthalmol. 2011 Jul;249(7):1021-8 Authors: Zhao T, Li Y, Tang L, Li Y, Fan F, Jiang B Abstract BACKGROUND: The majority of studies addressing traumatic optic neuropathy (TON) have focused on drugs, proteins, cytokines, and various surgical techniques. A recent study reported that transplantation of human umbilical cord blood stem cells (hUCBSCs) achieved therapeutic effects on TON, but the exact effects on optic nerve injury are still unknown, and the mechanisms underlying nerve protection remain poorly understood. METHODS: A total of 135 healthy Sprague-Dawley adult rats were randomly assigned to three groups: sham-surgery, model and transplantation, with 45 rats in each group. TON was induced in the model and transplantation groups via optic nerve crush injury. The crush injury was not performed in the sham-surgery group. Seven days after the injury, 10(6) hUCBSCs were injected into the rat vitreous cavity of transplantation group, and an equal volume of physiological saline was administered to the model and sham-surgery groups. Pathological observation of rat retina tissues was performed by hematoxylin-eosin (H&E) staining at days 3, 7, 14, 21 and 28 post-surgery. The number of retinal ganglion cells (RGCs) and mRNA expression levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) were assessed by the Fluorogold (FG) retrograde labeling and reverse transcriptase-polymerase chain reaction (RT-PCR) methods, respectively. RESULTS: The number of labeled RGCs and the expression of BDNF and GDNF mRNA obviously increased, and pathological injury was significantly ameliorated in the transplantation group compared to the model group (P < 0.05). CONCLUSIONS: Via intravitreal transplantation, the hUCBSCs resulted in a significant increase in the survival of the RGCs, and improved pathological changes in the rat retina, following TON. The protective mechanism is correlated with the continuous secretion of BDNF and GDNF in vivo of retina in optic nerve injury rats by the transplanted hUCBSCs. PMID: 21360302 [PubMed - indexed for MEDLINE]
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Related Articles Peptide amphiphiles and porous biodegradable scaffolds for tissue regeneration in the brain and spinal cord. Methods Mol Biol. 2011;726:259-81 Authors: Ellis-Behnke RG, Schneider GE Abstract Many promising strategies have been developed for controlling the release of drugs from scaffolds, yet there are still challenges that need to be addressed in order for these scaffolds to serve as successful treatments. The RADA4 self-assembling peptide spontaneously forms nanofibers, creating a scaffold-like tissue-bridging structure that provides a three-dimensional environment for the migration of living cells. We have found that RADA4: (1) facilitates the regeneration of axons in the brain of young and adult hamsters, leading to functional return of behavior and (2) demonstrates robust migration of host cells and growth of blood vessels and axons, leading to the repair of injured spinal cords in rats. PMID: 21424455 [PubMed - indexed for MEDLINE]
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Related Articles Transplantation of BDNF-secreting mesenchymal stem cells provides neuroprotection in chronically hypertensive rat eyes. Invest Ophthalmol Vis Sci. 2011 Jun;52(7):4506-15 Authors: Harper MM, Grozdanic SD, Blits B, Kuehn MH, Zamzow D, Buss JE, Kardon RH, Sakaguchi DS Abstract PURPOSE: To evaluate the ability of mesenchymal stem cells (MSCs) engineered to produce and secrete brain-derived neurotrophic factor (BDNF) to protect retinal function and structure after intravitreal transplantation in a rat model of chronic ocular hypertension (COH). METHODS: COH was induced by laser cauterization of trabecular meshwork and episcleral veins in rat eyes. COH eyes received an intravitreal transplant of MSCs engineered to express BDNF and green fluorescent protein (BDNF-MSCs) or just GFP (GFP-MSCs). Computerized pupillometry and electroretinography (ERG) were performed to assess optic nerve and retinal function. Quantification of optic nerve damage was performed by counting retinal ganglion cells (RGCs) and evaluating optic nerve cross-sections. RESULTS: After transplantation into COH eyes, BDNF-MSCs preserved significantly more retina and optic nerve function than GFP-MSC-treated eyes when pupil light reflex (PLR) and ERG function were evaluated. PLR analysis showed significantly better function (P = 0.03) in BDNF-MSC-treated eyes (operated/control ratio = 63.00% ± 11.39%) than GFP-MSC-treated eyes (operated/control ratio = 31.81% ± 9.63%) at 42 days after surgery. The BDNF-MSC-transplanted eyes also displayed a greater level of RGC preservation than eyes that received the GFP-MSCs only (RGC cell counts: BDNF-MSC-treated COH eyes, 112.2 ± 19.39 cells/section; GFP-MSC-treated COH eyes, 52.21 ± 11.54 cells/section; P = 0.01). CONCLUSIONS: The authors have demonstrated that lentiviral-transduced BDNF-producing MSCs can survive in eyes with chronic hypertension and can provide retina and optic nerve functional and structural protection. Transplantation of BDNF-producing stem cells may be a viable treatment strategy for glaucoma. PMID: 21498611 [PubMed - indexed for MEDLINE]
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Related Articles On the use of "stem cells" for optic nerve hypoplasia. Ophthalmology. 2011 May;118(5):795-6 Authors: American Association for Pediatric Ophthalmology & Strabismus (AAPOS) Research Committee PMID: 21539980 [PubMed - indexed for MEDLINE]
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Related Articles Effect of human umbilical cord blood stem cells on flash visual evoked potential in traumatic optic neuropathy in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2011 May;36(5):405-10 Authors: Zhu X, Jiang B, Zhang P, Zhou D Abstract OBJECTIVE: To investigate the effect of human umbilical cord blood stem cells on flash visual evoked potentials (F-VEP) of the traumatic optic neuropathy rats. METHODS: Forty-eight Sprague-Dawley rats were randomly divided into an injury group (Group A) and 3 treatment groups (Groups B, C, and D). A traumatic optic neuropathy model was built in Group A, and the rats in Groups B, C, and D were injected with the neurotrophic factor, human umbilical cord blood stem cells, and the mixture of the neurotrophic factor and human umbilical cord blood stem cells, respectively. F-VEP was recorded in both eyes of rats at the 1st h, 1st week, 2nd week, 3rd week, and 4th week after the optic nerve injury. RESULTS: At all time points, there were significant difference in the wave latency and amplitude between Group A and normal control eyes (P<0.01). The differences of the wave latency and amplitude between Group A and Groups B, C, and D were statistically significant at various time points after the injury except for the wave latency at the 1st h post-operation (P<0.05). The amplitude in Group D was higher while the latency was shorter than those of Group B at all time points since the 1st week (P<0.05). The comparisons at the same point in the remaining treatment groups were not significantly different (P<0.05). CONCLUSION: The mixture of human umbilical cord blood stem cells and neurotrophic factor has a promotion effect for the recovery of F-VEP of optic nerve in traumatic optic neuropathy in rats to some degrees. PMID: 21685695 [PubMed - indexed for MEDLINE]
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Related Articles Stem cells as a therapeutic tool for the blind: biology and future prospects. Proc Biol Sci. 2011 Oct 22;278(1721):3009-16 Authors: Singh MS, MacLaren RE Abstract Retinal degeneration due to genetic, diabetic and age-related disease is the most common cause of blindness in the developed world. Blindness occurs through the loss of the light-sensing photoreceptors; to restore vision, it would be necessary to introduce alternative photosensitive components into the eye. The recent development of an electronic prosthesis placed beneath the severely diseased retina has shown that subretinal stimulation may restore some visual function in blind patients. This proves that residual retinal circuits can be reawakened after photoreceptor loss and defines a goal for stem-cell-based therapy to replace photoreceptors. Advances in reprogramming adult cells have shown how it may be possible to generate autologous stem cells for transplantation without the need for an embryo donor. The recent success in culturing a whole optic cup in vitro has shown how large numbers of photoreceptors might be generated from embryonic stem cells. Taken together, these threads of discovery provide the basis for optimism for the development of a stem-cell-based strategy for the treatment of retinal blindness. PMID: 21813553 [PubMed - indexed for MEDLINE]
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Related Articles Olanzapine stimulates proliferation but inhibits differentiation in rat oligodendrocyte precursor cell cultures. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Dec 1;35(8):1950-6 Authors: Kimoto S, Okuda A, Toritsuka M, Yamauchi T, Makinodan M, Okuda H, Tatsumi K, Nakamura Y, Wanaka A, Kishimoto T Abstract In the developing brain, oligodendrocyte progenitor cells (OPCs) proliferate, migrate, and differentiate into mature oligodendrocytes (OLs) capable of myelinating axons. Recently, OPCs have been identified as an abundant and widespread population in the adult as well as in the developing animal. Current research indicates that these OPCs in the adult brain can proliferate and differentiate into myelinating OLs, albeit with different potentialities from those in developing animals. Multiple lines of evidence, from neuroimaging, postmortem, and genetic association studies, have implicated OL and myelin dysfunction in the pathogenesis of schizophrenia. If altered OL function is involved in pathogenesis, OPCs may thus respond to antipsychotic drugs during the recovery process. In the present study, we used primary OPC cultures from optic nerve of newborn Wistar rat pups to investigate the direct effects of haloperidol (HPD; a typical antipsychotic) and olanzapine (OLZ; an atypical antipsychotic) on the proliferation and differentiation of OPCs. Our results showed that 1) OLZ treatment significantly increased the number of viable OPCs when compared to HPD treatment at relatively high concentrations, 2) OLZ treatment suppressed the expression of myelin basic protein (MBP), and to a greater extent than HPD treatment, and 3) these pharmacological effects may be mediated via the ERK signaling pathway. Our findings suggest a glial mechanism for the antipsychotic action of OLZ, and a role for oligodendrocyte-lineage cells in the pathogenesis and treatment of schizophrenia. PMID: 21839137 [PubMed - indexed for MEDLINE]
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Related Articles Primitive stem cells derived from bone marrow express glial and neuronal markers and support revascularization in injured retina exposed to ischemic and mechanical damage. Stem Cells Dev. 2012 Jun 10;21(9):1488-500 Authors: Goldenberg-Cohen N, Avraham-Lubin BC, Sadikov T, Goldstein RS, Askenasy N Abstract Ischemic or mechanical injury to the optic nerve is an irreversible cause of vision loss, associated with limited regeneration and poor response to neuroprotective agents. The aim of this study was to assess the capacity of adult bone marrow cells to participate in retinal regeneration following the induction of anterior ischemic optic neuropathy (AION) and optic nerve crush (ONC) in a rodent model. The small-sized subset of cells isolated by elutriation and lineage depletion (Fr25lin(-)) was found to be negative for the neuroglial markers nestin and glial fibrillary acidic protein (GFAP). Syngeneic donor cells, identified by genomic marker in sex-mismatched transplants and green fluorescent protein, incorporated into the injured retina (AION and ONC) at a frequency of 0.35%-0.45% after intravenous infusion and 1.8%-2% after intravitreous implantation. Perivascular cells with astrocytic morphology expressing GFAP and vimentin were of the predominant lineage that engrafted after AION injury; 10%-18% of the donor cells incorporated in the retinal ganglion cell layer and expressed NeuN, Thy-1, neurofilament, and beta-tubulin III. The Fr25lin(-) cells displayed an excellent capacity to migrate to sites of tissue disruption and developed coordinated site-specific morphological and phenotypic neural and glial markers. In addition to cellular reconstitution of the injured retinal layers, these cells contributed to endothelial revascularization and apparently supported remodeling by secretion of insulin-like growth factor-1. These results suggest that elutriated autologous adult bone marrow-derived stem cells may serve as an accessible source for cellular reconstitution of the retina following injury. PMID: 21905921 [PubMed - indexed for MEDLINE]
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Related Articles 3-D spheroid culture of bone marrow mesenchymal stem cell of rhesus monkey with improved multi-differentiation potential to epithelial progenitors and neuron in vitro. Clin Experiment Ophthalmol. 2011 Nov;39(8):808-19 Authors: Jing Y, Jian-Xiong Y Abstract BACKGROUND: Bone mesenchymal stem cells are an attractive source of cells with potential applications in ocular regenerative medicine. However, the low differentiation efficiency in the traditional two-dimensional (2-D) culture system limits their application for clinical therapy. Here, we describe a simple and innovative 3-D culture environment and assess the potential for bone mesenchymal stem cells to differentiate into a variety of cell types in the 3-D system. METHODS: Bone mesenchymal stem cells of rhesus monkey were isolated and cultured using a density gradient centrifugation and adherence screening method. Cells at passage three were cultured by hanging drop and formed spheres. After 3 days, the spheres were collected and plated onto culture plates and maintained in a floating state by a rotary method for 10 days. Under appropriate induction conditions, the sphere cells were induced into adipocytes, osteoblasts, epithelial progenitors and neuronal cells. Differentiated cells were identified by histochemical staining, immunofluorescence and reverse transcription-polymerase chain reaction. RESULTS: Bone mesenchymal stem cells of rhesus monkey in the 3-D spheroid culture system acquired improved efficient multipotency for not only adipogenic and osteogeneic differentiation, but ectodermal epithelial progenitor-like cells and neuron-like cells compared with the 2-D culture system. CONCLUSION: Our 3-D spheroid culture system provides a useful technique to gain insight into the mechanisms of bone mesenchymal stem cells differentiation, and may have potential applications for the treatment of ocular surface and optic nerve disease. PMID: 22050567 [PubMed - indexed for MEDLINE]
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Related Articles Human induced pluripotent stem cells differentiation into oligodendrocyte progenitors and transplantation in a rat model of optic chiasm demyelination. PLoS One. 2011;6(11):e27925 Authors: Pouya A, Satarian L, Kiani S, Javan M, Baharvand H Abstract BACKGROUND: This study aims to differentiate human induced pluripotent stem cells (hiPSCs) into oligodendrocyte precursors and assess their recovery potential in a demyelinated optic chiasm model in rats. METHODOLOGY/PRINCIPAL FINDINGS: We generated a cell population of oligodendrocyte progenitors from hiPSCs by using embryoid body formation in a defined medium supplemented with a combination of factors, positive selection and mechanical enrichment. Real-time polymerase chain reaction and immunofluorescence analyses showed that stage-specific markers, Olig2, Sox10, NG2, PDGFRα, O4, A2B5, GalC, and MBP were expressed following the differentiation procedure, and enrichment of the oligodendrocyte lineage. These results are comparable with the expression of stage-specific markers in human embryonic stem cell-derived oligodendrocyte lineage cells. Transplantation of hiPSC-derived oligodendrocyte progenitors into the lysolecithin-induced demyelinated optic chiasm of the rat model resulted in recovery from symptoms, and integration and differentiation into oligodendrocytes were detected by immunohistofluorescence staining against PLP and MBP, and measurements of the visual evoked potentials. CONCLUSIONS/SIGNIFICANCE: These results showed that oligodendrocyte progenitors generated efficiently from hiPSCs can be used in future biomedical studies once safety issues have been overcome. PMID: 22125639 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell "tourism". Ophthalmology. 2011 Dec;118(12):2530-1 Authors: Miller NR PMID: 22136689 [PubMed - indexed for MEDLINE]
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Related Articles Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012 Feb;11(2):150-6 Authors: Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, Du MQ, Luan SL, Altmann DR, Thompson AJ, Compston A, Scott MA, Miller DH, Chandran S Abstract BACKGROUND: More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis. METHODS: Patients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5-6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov, number NCT00395200. FINDINGS: We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×10(6) cells per kg bodyweight (range 1·1-2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3-4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change -0·02 logMAR units, 95% CI -0·03 to -0·01; p=0·003) and visual evoked response latency (-1·33 ms, -2·44 to -0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm(2), 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio. INTERPRETATION: Autologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection. FUNDING: Medical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust. PMID: 22236384 [PubMed - indexed for MEDLINE]
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Related Articles Hemophagocytic lymphohistiocytosis with isolated central nervous system reactivation and optic nerve involvement. J Child Neurol. 2012 Oct;27(10):1336-9 Authors: Chong KW, Lee JH, Choong CT, Paeds MM, Chan DW, Fortier MV, Chan MY Abstract Hemophagocytic lymphohistiocytosis is a rare childhood disorder characterized by uncontrolled proliferation of benign lymphocytes and histiocytes in multiple organs. Neurological presentations of central nervous system involvement are highly variable. The authors present a case of familial hemophagocytic lymphohistiocytosis in an 8-month-old girl with isolated central nervous system reactivation and optic nerve involvement. She presented with fever and hepatosplenomegaly at 2 months of age. Genetic studies confirmed familial hemophagocytic lymphohistiocytosis. There were no clinical features of central nervous system involvement at presentation. While on maintenance chemotherapy awaiting bone marrow transplant, she presented with new-onset seizures. Magnetic resonance imaging of the brain revealed extensive areas of abnormal signal and a thickened and enhancing left optic nerve. Ocular manifestations of hemophagocytic lymphohistiocytosis have rarely been described. To the authors' knowledge, this is the first case report of magnetic resonance imaging findings of optic nerve involvement in a child with hemophagocytic lymphohistiocytosis. PMID: 22378674 [PubMed - indexed for MEDLINE]
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Related Articles [Glaucoma model for stem cell transplantation research in New Zealand white rabbits]. Dongwuxue Yanjiu. 2012 Apr;33(2):225-30 Authors: Guo LY, Wei JK, Yang SC, Wang ZB Abstract Glaucoma is a typical irreversible blind neurodegenerative disease for which there is no effective treatment for halting visual deterioration. The recent development of neural stem cells studies sheds light on a potential resolution for this disease. As a result, an appropriate glaucoma modeling method for stem cell transplantation study is needed. In the present study, Dexamethasone was injected unilaterally into the conjunctiva of New Zealand rabbit at the dose of 2.5 mg (5 mg/mL), three times a week. After eight weeks, the eye ground photography showed that the optic nerve head of the treated eye was expanded, and the blood vessel was geniculate compared to the control eye, while the ocular media remained transparent. The hematoxylin-eosin (HE) stain of the retinal nerve fiber layer (RNFL) sections showed optic neuron death in the treated eye. The Heidelberg Retina Tomography (HRT) results showed optic disk morphological changes consistent with the pathophysiology of glaucoma in the treated eye, including a decrease in the rim area (1.10±0.88) mm(2) and mean RNFL thickness (0.44±0.31) mm, and an increase in the cup/disk ratio 0.17±0.13. Then neural stem cells were injected into the vitreous body of the treated eye. After five months, surviving transplanted cells were observed. These results suggest a simple and reproducible chronic glaucoma model, which is appropriate for neural stem cell transplant research, has been successfully developed. PMID: 22467400 [PubMed - indexed for MEDLINE]
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Related Articles Visual observations of an American patient with Leber hereditary optic neuropathy after purported injections of stem cells in China. Arch Ophthalmol. 2012 Apr;130(4):532-4 Authors: Abukhalil F, Lam BL, Guy J PMID: 22491931 [PubMed - indexed for MEDLINE]
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Related Articles Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP-2 phosphorylation. Brain. 2012 Jun;135(Pt 6):1794-818 Authors: Petratos S, Ozturk E, Azari MF, Kenny R, Lee JY, Magee KA, Harvey AR, McDonald C, Taghian K, Moussa L, Mun Aui P, Siatskas C, Litwak S, Fehlings MG, Strittmatter SM, Bernard CC Abstract Multiple sclerosis involves demyelination and axonal degeneration of the central nervous system. The molecular mechanisms of axonal degeneration are relatively unexplored in both multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis. We previously reported that targeting the axonal growth inhibitor, Nogo-A, may protect against neurodegeneration in experimental autoimmune encephalomyelitis; however, the mechanism by which this occurs is unclear. We now show that the collapsin response mediator protein 2 (CRMP-2), an important tubulin-associated protein that regulates axonal growth, is phosphorylated and hence inhibited during the progression of experimental autoimmune encephalomyelitis in degenerating axons. The phosphorylated form of CRMP-2 (pThr555CRMP-2) is localized to spinal cord neurons and axons in chronic-active multiple sclerosis lesions. Specifically, pThr555CRMP-2 is implicated to be Nogo-66 receptor 1 (NgR1)-dependent, since myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced NgR1 knock-out (ngr1(-)(/)(-)) mice display a reduced experimental autoimmune encephalomyelitis disease progression, without a deregulation of ngr1(-)(/)(-) MOG(35-55)-reactive lymphocytes and monocytes. The limitation of axonal degeneration/loss in experimental autoimmune encephalomyelitis-induced ngr1(-)(/)(-) mice is associated with lower levels of pThr555CRMP-2 in the spinal cord and optic nerve during experimental autoimmune encephalomyelitis. Furthermore, transduction of retinal ganglion cells with an adeno-associated viral vector encoding a site-specific mutant T555ACRMP-2 construct, limits optic nerve axonal degeneration occurring at peak stage of experimental autoimmune encephalomyelitis. Therapeutic administration of the anti-Nogo(623-640) antibody during the course of experimental autoimmune encephalomyelitis, associated with an improved clinical outcome, is demonstrated to abrogate the protein levels of pThr555CRMP-2 in the spinal cord and improve pathological outcome. We conclude that phosphorylation of CRMP-2 may be downstream of NgR1 activation and play a role in axonal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Blockade of Nogo-A/NgR1 interaction may serve as a viable therapeutic target in multiple sclerosis. PMID: 22544872 [PubMed - indexed for MEDLINE]
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Related Articles Basic fibroblast growth factor potentiates myelin repair following induction of experimental demyelination in adult mouse optic chiasm and nerves. J Mol Neurosci. 2012 Sep;48(1):77-85 Authors: Dehghan S, Javan M, Pourabdolhossein F, Mirnajafi-Zadeh J, Baharvand H Abstract Induction of demyelination in the central nervous system induce the oligodendrocyte progenitors to proliferate, migrate, and differentiate for restoring new myelin sheathes around demyelinated axons. Factors which increase the response of endogenous progenitor cells could be used to improve remyelination. In the current study, the effect of bFGF on lysolecithin-induced demyelination and remyelination processes in mouse optic chiasm and nerves was investigated. Lysolecithin was injected into the optic chiasm of Balb/C mice. Two groups of animals received doses of bFGF (1 or 5 ng/kg i.p.) just before and every 3 days after lysolecithin injection. Delay and amplitude of visual evoked potential (VEP) waves were recorded as indices of axonal demyelination at 7th, 13th, and 28th days post-lesion. Myelin basic protein (MBP) and Olig2 gene expressions were studied as indices of myelination and oligodendrocyte precursors' recruitment into the lesion. Lysolecithin elongated delay of P1 wave and declined the amplitude of P1-N1 wave. Lysolecithin decreased MBP and increased Olig2 expression in different days post-lesion. Lysolecithin-induced changes in VEPs were partially ameliorated by endogenous repair. bFGF reduced the increased delay, increased the reduced amplitude of P1-N1 wave, increased MBP gene expression, and accelerated the increasing pattern of Olig2. bFGF seems to be able to potentiate the endogenous repair mechanisms of myelin. Its effect on demyelination and remyelination processes seems to be mediated by oligodendrocyte progenitor cells and their differentiation to myelinating cells. PMID: 22552714 [PubMed - indexed for MEDLINE]
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Related Articles Advances in treatment and management: immunologic and cell-based regenerative therapies. Invest Ophthalmol Vis Sci. 2012 May;53(5):2511-4 Authors: Friedlander M PMID: 22562853 [PubMed - indexed for MEDLINE]
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Related Articles Soluble adenylyl cyclase activity is necessary for retinal ganglion cell survival and axon growth. J Neurosci. 2012 May 30;32(22):7734-44 Authors: Corredor RG, Trakhtenberg EF, Pita-Thomas W, Jin X, Hu Y, Goldberg JL Abstract cAMP is a critical second messenger mediating activity-dependent neuronal survival and neurite growth. We investigated the expression and function of the soluble adenylyl cyclase (sAC, ADCY10) in CNS retinal ganglion cells (RGCs). We found sAC protein expressed in multiple RGC compartments including the nucleus, cytoplasm and axons. sAC activation increased cAMP above the level seen with transmembrane adenylate cyclase (tmAC) activation. Electrical activity and bicarbonate, both physiologic sAC activators, significantly increased survival and axon growth, whereas pharmacologic or siRNA-mediated sAC inhibition dramatically decreased RGC survival and axon growth in vitro, and survival in vivo. Conversely, RGC survival and axon growth were unaltered in RGCs from AC1/AC8 double knock-out mice or after specifically inhibiting tmACs. These data identify a novel sAC-mediated cAMP signaling pathway regulating RGC survival and axon growth, and suggest new neuroprotective or regenerative strategies based on sAC modulation. PMID: 22649251 [PubMed - indexed for MEDLINE]
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Related Articles [Neurogenesis in the central nervous system and prospects of regenerative neurology]. Zh Nevrol Psikhiatr Im S S Korsakova. 2012;112(1):4-13 Authors: Iarygin KN, Iarygin VN Abstract Discovery of neural stem cells (NSC) providing homeostatic adaptive and injury induced neural regeneration in the CNS of adult mammals, including Homo sapiens, is the most prominent accomplishment over the recent period of neurobiology research. NSC are concentrated in two neurogenic zones - side walls of lateral ventricle (subventricular zone) and hippocampal dentate gyrus (subgranular zone). In addition, new neurons may develop from other undifferentiated cells scattered throughout various CNS regions. Neurogenesis in adult mammals is an intensive process that leads to renewal of interneuron populations in such brain regions as olfactory bulbs and hippocampus by 5 and more percent per month. Advances in regenerative neurobiology may serve the foundation for the development of totally new technologies of treatment brain and spinal cord, as well as retina and optic nerve injuries and diseases based on the stimulation of reparative neurogenesis, design of conditions permissive for regeneration of nervous and glial cells and growth of nervous fibers, and on blocking factors inhibiting those two former processes. PMID: 22678669 [PubMed - indexed for MEDLINE]
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Related Articles Rhino-orbital-cerebral mucormycosis. Curr Infect Dis Rep. 2012 Aug;14(4):423-34 Authors: Gamaletsou MN, Sipsas NV, Roilides E, Walsh TJ Abstract This review focuses on sinus, sino-orbital, and rhinocerebral infection caused by the Mucorales. As the traditional term of "rhinocerebral" mucormycosis omits the critical involvement of the eye, the more comprehensive term as rhino-orbital-cerebral mucormycosis (ROCM) is used. The most common underlying illnesses of ROCM are diabetes mellitus, hematological malignancies, hematopoietic stem cell transplantation, and solid organ transplantation. Sporangiospores are deposited in the nasal turbinates and paranasal sinuses in immunocompromised patients. Qualitative and quantitative abnormalities of neutrophils, monocytes and macrophages increase the risk for development of mucormycosis. Altered iron metabolism also is a critical factor in the pathogenesis of patients with diabetes mellitus who are at risk for ROCM. Angioinvasion with thrombosis and tissue necrosis is a key pathophysiological feature of human Mucorales infection. The ethmoid sinus is a critical site from which sinus mucormycosis may extend through the lamina papyracea into the orbit, extraocular muscles, and optic nerve. The brain may be seeded by invasion of the ethmoidal and orbital veins, which drain into the cavernous sinuses. Diplopia and ophthalmoplegia may be the earliest manifestations of cavernous sinus syndrome before changes are apparent on diagnostic imaging modalities. Negative diagnostic imaging does not exclude cavernous sinus mucormycosis. Mucormycosis of the maxillary sinus has a constellation of clinical features that are different from that of ethmoid sinus mucormycosis. A painful black necrotic ulceration may develop on the hard palate, indicating extension from the maxillary sinus into the oral cavity. Orbital apex syndrome is an ominous complication of mucormycosis of the orbit. Once within the orbital compartment, organisms may extend posteriorly to the optic foramen, where the ophthalmic artery, ophthalmic nerve and optic nerve are threatened by invasion, edema, inflammation and necrosis. Early diagnosis of sinus mucormycosis is critical for prevention of extension to orbital and cerebral tissues. Optimal therapy requires a multidisciplinary approach that relies on prompt institution of appropriate antifungal therapy with amphotericin B, reversal of underlying predisposing conditions, and, where possible, surgical debridement of devitalized tissue. Outcomes are highly dependent upon the degree of immunosuppression, site and extent of infection, timeliness of therapy, and type of treatment provided. New modalities for early diagnosis and therapeutic intervention are critically needed for improved outcome of patients with ROCM. PMID: 22684277 [PubMed]
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Related Articles A simplified technique for in situ excision of cornea and evisceration of retinal tissue from human ocular globe. J Vis Exp. 2012;(64):e3765 Authors: Parekh M, Ferrari S, Di Iorio E, Barbaro V, Camposampiero D, Karali M, Ponzin D, Salvalaio G Abstract Enucleation is the process of retrieving the ocular globe from a cadaveric donor leaving the rest of the globe undisturbed. Excision refers to the retrieval of ocular tissues, especially cornea, by cutting it separate from the ocular globe. Evisceration is the process of removing the internal organs referred here as retina. The ocular globe consists of the cornea, the sclera, the vitreous body, the lens, the iris, the retina, the choroid, muscles etc (Suppl. Figure 1). When a patient is suffering from corneal damage, the cornea needs to be removed and a healthy one must be transplanted by keratoplastic surgeries. Genetic disorders or defects in retinal function can compromise vision. Human ocular globes can be used for various surgical procedures such as eye banking, transplantation of human cornea or sclera and research on ocular tissues. However, there is little information available on human corneal and retinal excision, probably due to the limited accessibility to human tissues. Most of the studies describing similar procedures are performed on animal models. Research scientists rely on the availability of properly dissected and well-conserved ocular tissues in order to extend the knowledge on human eye development, homeostasis and function. As we receive high amount of ocular globes out of which approximately 40% (Table 1) of them are used for research purposes, we are able to perform huge amount of experiments on these tissues, defining techniques to excise and preserve them regularly. The cornea is an avascular tissue which enables the transmission of light onto the retina and for this purpose should always maintain a good degree of transparency. Within the cornea, the limbus region, which is a reservoir of the stem cells, helps the reconstruction of epithelial cells and restricts the overgrowth of the conjunctiva maintaining corneal transparency and clarity. The size and thickness of the cornea are critical for clear vision, as changes in either of them could lead to distracted, unclear vision. The cornea comprises of 5 layers; a) epithelium, b) Bowman's layer, c) stroma, d) Descemet's membrane and e) endothelium. All layers should function properly to ensure clear vision(4,5,6). The choroid is the intermediate tunic between the sclera and retina, bounded on the interior by the Bruch's membrane and is responsible for blood flow in the eye. The choroid also helps to regulate the temperature and supplies nourishment to the outer layers of the retina(5,6). The retina is a layer of nervous tissue that covers the back of the ocular globe (Suppl. Figure 1) and consists of two parts: a photoreceptive part and a non-receptive part. The retina helps to receive the light from the cornea and lens and converts it into the chemical energy eventually transmitted to the brain with help of the optic nerve(5,6). The aim of this paper is to provide a protocol for the dissection of corneal and retinal tissues from human ocular globes. Avoiding cross-contamination with adjacent tissues and preserving RNA integrity is of fundamental importance as such tissues are indispensable for research purposes aimed at (i) characterizing the transcriptome of the ocular tissues, (ii) isolating stem cells for regenerative medicine projects, and (iii) evaluating histological differences between tissues from normal/affected subjects. In this paper we describe the technique we currently use to remove the cornea, the choroid and retinal tissues from an ocular globe. Here we provide a detailed protocol for the dissection of the human ocular globe and the excision of corneal and retinal tissues. The accompanying video will help researchers to learn an appropriate technique for the retrieval of precious human tissues which are difficult to find regularly. PMID: 22733120 [PubMed - indexed for MEDLINE]
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Related Articles High-dose chemotherapy followed by stem cell transplantation in the management of retinoblastoma: a systematic review. Hematol Oncol Stem Cell Ther. 2012;5(2):107-17 Authors: Jaradat I, Mubiden R, Salem A, Abdel-Rahman F, Al-Ahmad I, Almousa A Abstract BACKGROUND AND OBJECTIVES: In recent years, there has been an increasing role for stem cell transplantation in the management of retinoblastoma. The aim of this study was to systematically review the role high-dose chemotherapy followed by stem cell transplantation in the treatment of patients with metastatic or relapsed, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension. DESIGN: Systematic literature review. METHODS: We performed an extensive PubMed database search on 25 February 2012 for studies describing the use of high-dose chemotherapy followed by stem cell transplantation in the management of patients with retinoblastoma. RESULTS: We located 15 studies that met the inclusion criteria and that included 101 patients. Following treatment for metastatic and relapsed disease, 44 of 77 patients (57.1%) were alive with no evidence of disease at the time of follow-up. However, a higher rate of local relapse developed in patients with CNS metastases (73.1%), which dropped to 47.1% in patients who received thiotepa. In patients with trilateral or bilateral advanced retinoblastoma, 5 of 7 (71.4%) with reported outcome data were alive with no evidence of disease at the time of follow-up. In patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension, 6 of 7 patients (85.7%) were alive with no evidence of disease at the time of follow-up. CONCLUSIONS: Durable tumor control is possible in patients with non-CNS metastases, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension. Patients with CNS metastases require thiotepa to improve tumor control. PMID: 22828375 [PubMed - indexed for MEDLINE]
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Related Articles Effects of crystallin-β-b2 on stressed RPE in vitro and in vivo. Graefes Arch Clin Exp Ophthalmol. 2013 Jan;251(1):63-79 Authors: Böhm MR, Melkonyan H, Oellers P, Thanos S Abstract BACKGROUND: Crystallins are thought to play a cytoprotective role in conditions of cellular stress. The aim of this study was to determine the effects of crystallin-β-b2 (cryβ-b2) and crystallin-β-b3 (cryβ-b3) on ARPE-19 cells in vitro and on the retinal pigment epithelium (RPE) in vivo. METHODS: The influence of cryβ-b2 and cryβ-b3 on the viability, proliferation and dying of ARPE-19 was measured by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, bromo-2-deoxyuridine assay and life/death assay. The expressions of cryβ-b2, cryβ-b3, glial-derived neurotrophic factor (GDNF), and galectin-3 (Gal-3) in ARPE-19 cells were evaluated using immunohistochemistry (IHC), Western blotting (WB) and real-time-quantitative-PCR (qRT-PCR). To evaluate the response of cryβ-b2 and cryβ-b3 to stressed ARPE-19 cells, the cells were exposed to UV-light. In a rat model, cryβ-b2-expressing neural progenitor cells (cryβ-b2-NPCs) were injected intravitreally after retinal stress induced by optic nerve axotomy to examine whether they influence the RPE. Protein expression was examined 2 and 4 weeks postsurgery using IHC and WB. RESULTS: Detectable alterations of GDNF, and Gal-3 were found in ARPE-19 cells upon exposure to UV light. Adding the crystallins to the medium promoted proliferation and increased viability of ARPE-19 cells in vitro. The obtained data support the view that these crystallins possess epithelioprotective properties. Likewise, in vivo, intravitreally injected cryβ-b2 and transplanted cryβ-b2-NPCs protected RPE from indirectly induced stress. CONCLUSIONS: The data suggest that the RPE response to retinal ganglion cell denegeration is mediated via crystallins, which may thus be used therapeutically. PMID: 23073841 [PubMed - indexed for MEDLINE]
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Related Articles Crystallin-β-b2-overexpressing NPCs support the survival of injured retinal ganglion cells and photoreceptors in rats. Invest Ophthalmol Vis Sci. 2012 Dec;53(13):8265-79 Authors: Böhm MR, Pfrommer S, Chiwitt C, Brückner M, Melkonyan H, Thanos S Abstract PURPOSE: Crystallin β-b2 (crybb2) is known to support the regeneration of retinal ganglion cell (RGC) axons in culture. We investigated whether neuronal progenitor cells (NPCs) overexpressing crybb2 (crybb2-NPC) affect secondary retinal degeneration due to optic nerve crush in vivo. METHODS: NPCS were produced by dissociation and propagation of rat embryonic neural tube and eye primordial cells at embryonic days 13.5 and 15. Retinal degeneration was induced by injured optic nerve crush (BY suture, 20 seconds). Several groups were built: crybb2-NPC were injected into the vitreous body, while the Controls were comprised of recombinant crybb2-injected and PBS-injected groups. The eyes, in particular the retina, were analyzed by immunohistochemistry and Western blotting for different antigens at 2 and 4 weeks after surgery. RESULTS: At 2 and 4 weeks post surgery, crybb2-NPC resided within the vitreoretinal compartment, and were persistently nestin-positive throughout the experimental period. The cells stained positive for various neurotrophins and acted as "living" cell factories to support the survival of injured RGCs. The crybb2-NPC migrated throughout the eye structures and sometimes became integrated within the tissue. Most of the ocular cells responded to the appearance of crybb2-NPC with marked changes of certain proteins, including Iba-1 (microglia), vimentin (glial cells), and rhodopsin (photoreceptors). Photoreceptors also displayed a better survival after crybb2-NPC injection compared to control groups. CONCLUSIONS: Crybb2-NPC exert beneficial effects on the vitreoretinal compartment, which suggests that modified crybb2-NPC could be used in a novel strategy for the treatment of degenerative vitreoretinal diseases. However, future studies must determine the safety of in vivo administration of crybb2-NPC. PMID: 23132806 [PubMed - indexed for MEDLINE]
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Related Articles Adult mice transplanted with embryonic retinal progenitor cells: new approach for repairing damaged optic nerves. Mol Vis. 2012;18:2658-72 Authors: Cho JH, Mao CA, Klein WH Abstract PURPOSE: Retinal ganglion cell (RGC) death and optic nerve degeneration are complex processes whose underlying molecular mechanisms are only vaguely understood. Treatments commonly used for optic nerve degeneration have little long-term value and only prolong degeneration. Recent advances in stem cell replacement therapy offer new ways to overcome RGC loss by transferring healthy cells into eyes of afflicted individuals. However, studies on stem cell replacement for optic nerve degeneration are hampered by limitations of the available animal models, especially genetic models. We have developed a mouse model in which RGCs are genetically ablated in adult mice with subsequent degeneration of the optic nerve. In the study reported here, we used this model to determine whether embryonic retinal progenitor cells (RPCs) removed from donor retinas when RPCs are committing to an RGC fate could restore lost RGCs. METHODS: We used the RGC-depleted model as a host for transplanting donor green fluorescent protein (GFP)-labeled RPCs from embryonic retinas that are maximally expressing Atoh7, a basic helix-loop-helix gene essential for RGC specification. Dissociated GFP-labeled RPCs were characterized in situ by immunolabeling with antibodies against proteins known to be expressed in RPCs at embryonic day (E)14.5. Dissociated retinal cells were injected into the vitreous of one eye of RGC-depleted mice at two to six months of age. The injected and non-injected retinas were analyzed for gene expression using immunolabeling, and the morphology of optic nerves was assessed visually and with histological staining at different times up to four months after injection. RESULTS: We demonstrate the successful transfer of embryonic GFP-labeled RPCs into the eyes of RGC-depleted mice. Many transplanted RPCs invaded the ganglion cell layer, but the efficiency of the invasion was low. GFP-labeled cells within the ganglion cell layer expressed genes associated with early and late stages of RGC differentiation, including Pou4f1, Pou4f2, NFL, Map2, and syntaxin. Several GFP-labeled cells were detected within the injected optic nerves of RGC-depleted mice, and in most cases, we observed a significant increase in the thickness of the RPC-injected optic nerves compared with non-injected controls. We also observed more bundled axons emanating from RPC-injected retinas compared with RGC-depleted controls. CONCLUSIONS: The results offer a new approach for regenerating damaged optic nerves and indicate that a significant number of E14.5 RPCs are able to differentiate into RGCs in the foreign environment of the adult retina. However, the proportion of RPCs that populated the ganglion cell layer and contributed to the optic nerve was not sufficient to account for the increased thickness and higher number of axons. The results support the hypothesis that the injected E14.5 RPCs are contributing autonomously and non-autonomously to restoring damaged optic nerves. PMID: 23170059 [PubMed - indexed for MEDLINE]
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Related Articles Human Müller glia with stem cell characteristics differentiate into retinal ganglion cell (RGC) precursors in vitro and partially restore RGC function in vivo following transplantation. Stem Cells Transl Med. 2012 Mar;1(3):188-99 Authors: Singhal S, Bhatia B, Jayaram H, Becker S, Jones MF, Cottrill PB, Khaw PT, Salt TE, Limb GA Abstract Müller glia with stem cell characteristics have been identified in the adult human eye, and although there is no evidence that they regenerate retina in vivo, they can be induced to grow and differentiate into retinal neurons in vitro. We differentiated human Müller stem cells into retinal ganglion cell (RGC) precursors by stimulation with fibroblast growth factor 2 together with NOTCH inhibition using the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT). Differentiation into RGC precursors was confirmed by gene and protein expression analysis, changes in cytosolic [Ca(2+)] in response to neurotransmitters, and green fluorescent protein (GFP) expression by cells transduced with a transcriptional BRN3b-GFP reporter vector. RGC precursors transplanted onto the inner retinal surface of Lister hooded rats depleted of RGCs by N-methyl-d-aspartate aligned onto the host RGC layer at the site of transplantation but did not extend long processes toward the optic nerve. Cells were observed extending processes into the RGC layer and expressing RGC markers in vivo. This migration was observed only when adjuvant anti-inflammatory and matrix degradation therapy was used for transplantation. RGC precursors induced a significant recovery of RGC function in the transplanted eyes as determined by improvement of the negative scotopic threshold response of the electroretinogram (indicative of RGC function). The results suggest that transplanted RGC precursors may be capable of establishing local interneuron synapses and possibly release neurotrophic factors that facilitate recovery of RGC function. These cells constitute a promising source of cells for cell-based therapies to treat retinal degenerative disease caused by RGC dysfunction. PMID: 23197778 [PubMed - indexed for MEDLINE]
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Related Articles The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse. Brain. 2012 Dec;135(Pt 12):3599-613 Authors: Sarzi E, Angebault C, Seveno M, Gueguen N, Chaix B, Bielicki G, Boddaert N, Mausset-Bonnefont AL, Cazevieille C, Rigau V, Renou JP, Wang J, Delettre C, Brabet P, Puel JL, Hamel CP, Reynier P, Lenaers G Abstract Dominant optic atrophy is a rare inherited optic nerve degeneration caused by mutations in the mitochondrial fusion gene OPA1. Recently, the clinical spectrum of dominant optic atrophy has been extended to frequent syndromic forms, exhibiting various degrees of neurological and muscle impairments frequently found in mitochondrial diseases. Although characterized by a specific loss of retinal ganglion cells, the pathophysiology of dominant optic atrophy is still poorly understood. We generated an Opa1 mouse model carrying the recurrent Opa1(delTTAG) mutation, which is found in 30% of all patients with dominant optic atrophy. We show that this mouse displays a multi-systemic poly-degenerative phenotype, with a presentation associating signs of visual failure, deafness, encephalomyopathy, peripheral neuropathy, ataxia and cardiomyopathy. Moreover, we found premature age-related axonal and myelin degenerations, increased autophagy and mitophagy and mitochondrial supercomplex instability preceding degeneration and cell death. Thus, these results support the concept that Opa1 protects against neuronal degeneration and opens new perspectives for the exploration and the treatment of mitochondrial diseases. PMID: 23250881 [PubMed - indexed for MEDLINE]
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Related Articles Adenosine A1 receptor agonist, N6-cyclohexyladenosine, protects myelin and induces remyelination in an experimental model of rat optic chiasm demyelination; electrophysiological and histopathological studies. J Neurol Sci. 2013 Feb 15;325(1-2):22-8 Authors: Asghari AA, Azarnia M, Mirnajafi-Zadeh J, Javan M Abstract Chronic demyelinated lesions and subsequent functional impairment are resulted from eventual failure of remyelination process as seen in multiple sclerosis. Activation of adenosine A1 receptor is reported to be effective on neural stem cells (NSCs) proliferation and oligodendrocytes differentiation. Therefore, this study attempted to investigate the effect of A1 receptor agonist N6-cyclohexyladenosine (CHA), on lysolecithin (LPC) induced demyelination and remyelination in rat optic chiasm. The experiments were carried out on male Wistar rats using visual evoked potential recording, myelin staining by Luxol fast blue and histological evaluation of demyelinated and remyelinated axons within the area of lesion. CHA was administrated i.c.v. during demyelination or remyelination phases. As revealed by myelin staining, the most extent of demyelination occurred at 7th day post-lesion (dpl 7), but gradually myelination was restored toward control during days 14-28. VEP P1-latency and P1-N1 amplitude showed widespread demyelination on dpl 7 and 14 which consequently was reversed during days 14-28 post lesion. I.c.v. treatment of animals with CHA during demyelination phase (days 0-13) reduced the extent of demyelination. During remyelination phase (days 14-28), CHA was able to increase remyelination in both electrophysiological and histopathological studies. The effects of CHA seem to be due to its protective effect on myelinating cells and its regenerative effect through potentiating endogenous neural progenitors. PMID: 23260322 [PubMed - indexed for MEDLINE]
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Related Articles Results of a multicenter prospective study on the postoperative treatment of unilateral retinoblastoma after primary enucleation. J Clin Oncol. 2013 Apr 10;31(11):1458-63 Authors: Aerts I, Sastre-Garau X, Savignoni A, Lumbroso-Le Rouic L, Thebaud-Leculée E, Frappaz D, Coze C, Thomas C, Gauthier-Villars M, Lévy-Gabriel C, Brisse HJ, Desjardins L, Doz F Abstract PURPOSE: The objective of this prospective study was to assess overall survival and event-free survival in patients with intraocular unilateral retinoblastoma (Reese-Ellsworth group V) treated by primary enucleation with or without adjuvant therapy depending on histopathologic risk factors. PATIENTS AND METHODS: Patients (n = 123) were divided into three groups on the basis of risk factors for extraocular relapse and metastasis assessed on centralized histologic examination of enucleated eyes. Group 1 (n = 70) had minimal or no choroidal involvement and/or prelaminar or no optic nerve involvement and received no adjuvant therapy. Group 2 (n = 52) had massive choroidal involvement and/or intra- or retrolaminar optic nerve involvement and/or anterior segment involvement and received four courses of adjuvant chemotherapy. Group 3 (n = 1) had invasion of the surgical margin of the optic nerve and/or microscopic extrascleral involvement and received six courses of adjuvant chemotherapy with intrathecal thiotepa, consolidation chemotherapy, and autologous stem-cell rescue. Genetic testing was also performed. RESULTS: Median follow-up for the 123 patients was 71 months. No disease progression, relapse, or distant metastasis occurred during follow-up. No second malignancies occurred. This requires confirmation with longer follow-up. Secondary bilateralization occurred in two patients with identified RB1 germline mutation. Adjuvant chemotherapy was well tolerated, with limited toxicity. Molecular testing found constitutional RB1 gene mutations in only nine of 100 evaluated patients. CONCLUSION: The survival rate of 100% was excellent, including 57% of patients who received no adjuvant therapy, suggesting that chemotherapy could be de-escalated in some patients, especially those with massive choroidal involvement. PMID: 23460706 [PubMed - indexed for MEDLINE]
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Related Articles Tissue engineering the retinal ganglion cell nerve fiber layer. Biomaterials. 2013 Jun;34(17):4242-50 Authors: Kador KE, Montero RB, Venugopalan P, Hertz J, Zindell AN, Valenzuela DA, Uddin MS, Lavik EB, Muller KJ, Andreopoulos FM, Goldberg JL Abstract Retinal degenerative diseases, such as glaucoma and macular degeneration, affect millions of people worldwide and ultimately lead to retinal cell death and blindness. Cell transplantation therapies for photoreceptors demonstrate integration and restoration of function, but transplantation into the ganglion cell layer is more complex, requiring guidance of axons from transplanted cells to the optic nerve head in order to reach targets in the brain. Here we create a biodegradable electrospun (ES) scaffold designed to direct the growth of retinal ganglion cell (RGC) axons radially, mimicking axon orientation in the retina. Using this scaffold we observed an increase in RGC survival and no significant change in their electrophysiological properties. When analyzed for alignment, 81% of RGCs were observed to project axons radially along the scaffold fibers, with no difference in alignment compared to the nerve fiber layer of retinal explants. When transplanted onto retinal explants, RGCs on ES scaffolds followed the radial pattern of the host retinal nerve fibers, whereas RGCs transplanted directly grew axons in a random pattern. Thus, the use of this scaffold as a cell delivery device represents a significant step towards the use of cell transplant therapies for the treatment of glaucoma and other retinal degenerative diseases. PMID: 23489919 [PubMed - indexed for MEDLINE]
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Related Articles Hippocampal avoidance with volumetric modulated arc therapy in melanoma brain metastases - the first Australian experience. Radiat Oncol. 2013;8:62 Authors: Awad R, Fogarty G, Hong A, Kelly P, Ng D, Santos D, Haydu L Abstract PURPOSE: Volumetric modulated arc therapy (VMAT) can deliver intensity modulated radiotherapy (IMRT) like dose distributions in a short time; this allows the expansion of IMRT treatments to palliative situations like brain metastases (BMs). VMAT can deliver whole brain radiotherapy (WBRT) with hippocampal avoidance and a simultaneous integrated boost (SIB) to achieve stereotactic radiotherapy (SRT) for BMs. This study is an audit of our experience in the treatment of brain metastases with VMAT in our institution. METHODS AND MATERIALS: Metastases were volumetrically contoured on fused diagnostic gadolinium enhanced T1 weighted MRI/planning CT images. Risk organs included hippocampus, optic nerve, optic chiasm, eye, and brain stem. The hippocampi were contoured manually as one paired organ with assistance from a neuroradiologist. WBRT and SIB were integrated into a single plan. RESULTS: Thirty patients with 73 BMs were treated between March 2010 and February 2012 with VMAT. Mean follow up time was 3.5 months. For 26 patients, BMs arose from primary melanoma and for the remaining four patients from non-small cell lung cancer (n= 2), primary breast cancer, and sarcoma. Mean age was 60 years. The male to female ratio was 2:1. Five patients were treated without hippocampal avoidance (HA) intent. The median WBRT dose was 31 Gy with a median SIB dose for BMs of 50 Gy, given over a median of 15 fractions. Mean values for BMs were as follows: GTV = 6.9 cc, PTV = 13.3 cc, conformity index = 8.6, homogeneity index = 1.06. Mean and maximum hippocampus dose was 20.4 Gy, and 32.4 Gy, respectively, in patients treated with HA intent. Mean VMAT treatment time from beam on to beam off for one fraction was 3.43 minutes, which compared to WBRT time of 1.3 minutes. Twenty out of 25 assessable lesions at the time of analysis were controlled. Treatment was well tolerated; grade 4 toxicity was reported in one patient. The median overall survival was 9.40 months CONCLUSIONS: VMAT for BMs is feasible, safe and associated with a similar survival times and toxicities to conventional SRT+/-WBRT. The advantage of VMAT is that WBRT and SRT can be delivered at the same time on one machine. PMID: 23497418 [PubMed - indexed for MEDLINE]
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Related Articles Role of B lymphoma Mo-MLV insertion region 1 in the oncogenic behavior of retinoblastomas. Mol Vis. 2013;19:561-74 Authors: Ren R, Liu W, Huang L, Liu DT, Choy KW, Shi J, Zhao J, Zhao B, Guan M, Shields CL, Pang CP, Li B, Yam GH Abstract PURPOSE: This study investigated the relationship between B lymphoma Mo-MLV insertion region 1 (BMI-1)--a polycomb protein for stem cell self-renewal and proliferation--and the clinicopathological parameters of human retinoblastomas, including differentiation status and retinal tissue invasion, as well as the effects of BMI-1 on retinoblastoma Y79 cells. METHODS: Thirty-four archived human retinoblastoma samples were recruited for BMI-1 immunohistochemistry. The percentage of BMI-1-expressing cells was scored by independent pathologists and the data were correlated with the clinical features. Y79 cells were transfected to overexpress or specifically inhibit BMI-1 for cell proliferation, propidium iodide cell cycle and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis analyses, multicellular sphere formation assay, and gene expression study. RESULTS: BMI-1 was widely expressed in human retinoblastomas. Higher percentages of BMI-1-expressing cells were selectively limited to undifferentiated tumors and those tumors undergoing invasion to the optic nerve and choroid. However, there was no difference in BMI-1 expression in retinoblastoma retinas with or without tumor invasion. In Y79 cells, BMI-1 stimulated cell proliferation and suppressed apoptosis with reduced p14ARF and p16INK4 expression, along with upregulation of proliferating cell nuclear antigens cyclin D1 and D2. In contrast, silencing BMI-1 reversed these changes. It also upregulated CHX10 and Rx, but not other retinal development-related genes, including nestin and neurofilament M. CONCLUSIONS: Our work indicates that BMI-1 might render important oncogenic property of retinoblastomas and it could be a therapeutic target for the cancer treatment. PMID: 23559850 [PubMed - indexed for MEDLINE]
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Related Articles Ocular manifestations and visual functions in patients with Fanconi anaemia. Acta Ophthalmol. 2014 Mar;92(2):171-8 Authors: Törnquist AL, Martin L, Winiarski J, Fahnehjelm KT Abstract PURPOSE: Fanconi anaemia (FA) is a multisystemic disorder with ocular implications. This study aims to describe visual function, ocular characteristics and visual processing skills in patients with FA after haematopoietic stem cell transplantation. METHODS: Ten patients with FA, ages 8-17 years, underwent ophthalmological examinations, corneal, periocular and fundus photography, visual evoked potentials (VEPs), visual fields and ocular motor and visual processing information tests. RESULTS: Best-corrected decimal visual acuity was ≥0.65 in all 20 eyes. Microcornea was present in 18 of 18 eyes, short axial lengths in six of six eyes, steep corneal curvatures in four of six eyes, ptosis in 14 of 16 eyes, short palpebral fissures in 15 of 16 eyes and hypotelorism in three of seven patients. Optic disc areas were smaller in patients with FA compared to controls (p = 0.0003 right, p = 0.0003 left eye). Visual fields were abnormal in 4 of 18 eyes, while VEP was abnormal in 1 of 20 eyes. Eight patients had ocular motor dysfunction, while nine of 10 patients showed delay in visual processing skills. CONCLUSION: Patients with FA can present with microcornea, microphthalmia, ptosis, steep corneal curvatures, small optic discs, ptosis and delay in visual processing skills. Detailed ophthalmological and visual processing skills assessments and developmental investigations are important to detect impairments and facilitate appropriate support. PMID: 23648176 [PubMed - indexed for MEDLINE]
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Related Articles Hypoxia mediated expression of stem cell markers in VHL-associated hemangioblastomas. Biochem Biophys Res Commun. 2013 Aug 16;438(1):71-7 Authors: Ponnaluri VK, Vavilala DT, Prakash S, Mukherji M Abstract Hemangioblastomas of the retina, central nervous system, and kidney are observed in patients with mutations in the von Hippel-Lindau (VHL) tumor suppressor gene. Mutations in the VHL lead to constitutive activation of hypoxia-inducible-factor (HIF) pathway. HIF-mediated expression of pro-angiogenic genes causes extensive pathological neovascularization in hemangioblastomas. A number of studies have shown coexistence of pro-angiogenic and stem cell markers in 'tumorlet-like stromal cells' in the retinal and optic nerve hemangioblastomas, leading to suggestions that hemangioblastomas originate from developmentally arrested stem cells or embryonic progenitors. Since recent studies have shown that the HIF pathway also plays a role in the maintenance/de-differentiation of normal and cancerous stem cells, we evaluated the role of the HIF pathway in the expression of stem cell markers in VHL-/- renal cell carcinoma cells under normoxia or VHL+/+ retinal pigment epithelial cells under hypoxia. Here we show that the expression of stem cell markers in hemangioblastomas is due to activation of the HIF pathway. Further, we show that honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources, blocks the expression of stem cell markers. Our results show the mechanism for the cytological origin of neoplastic stromal cells in hemangioblastomas, and suggest that inhibition of the HIF pathway is an attractive strategy for the treatment of hemangioblastomas. PMID: 23872148 [PubMed - indexed for MEDLINE]
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Related Articles Neural stem cell sparing by linac based intensity modulated stereotactic radiotherapy in intracranial tumors. Radiat Oncol. 2013;8:187 Authors: Oehler J, Brachwitz T, Wendt TG, Banz N, Walther M, Wiezorek T Abstract BACKGROUND: Neurocognitive decline observed after radiotherapy (RT) for brain tumors in long time survivors is attributed to radiation exposure of the hippocampus and the subventricular zone (SVZ). The potential of sparing capabilities for both structures by optimized intensity modulated stereotactic radiotherapy (IMSRT) is investigated. METHODS: Brain tumors were irradiated by stereotactic 3D conformal RT or IMSRT using m3 collimator optimized for PTV and for sparing of the conventional OARs (lens, retina, optic nerve, chiasm, cochlea, brain stem and the medulla oblongata). Retrospectively both hippocampi and SVZ were added to the list of OAR and their dose volume histograms were compared to those from two newly generated IMSRT plans using 7 or 14 beamlets (IMSRT-7, IMSRT-14) dedicated for optimized additional sparing of these structures. Conventional OAR constraints were kept constant. Impact of plan complexity and planning target volume (PTV) topography on sparing of both hippocampi and SVZ, conformity index (CI), the homogeneity index (HI) and quality of coverage (QoC) were analyzed. Limits of agreement were used to compare sparing of stem cell niches with either IMSRT-7 or IMSRT-14. The influence of treatment technique related to the topography ratio between PTV and OARs, realized in group A-D, was assessed by a mixed model. RESULTS: In 47 patients CI (p ≤  0.003) and HI (p  <  0.001) improved by IMSRT-7, IMSRT-14, QoC remained stable (p  ≥  0.50) indicating no compromise in radiotherapy. 90% of normal brain was exposed to a significantly higher dose using IMSRT. IMSRT-7 plans resulted in significantly lower biologically effective doses at all four neural stem cell structures, while contralateral neural stem cells are better spared compared to ipsilateral. A further increase of the number of beamlets (IMSRT-14) did not improve sparing significantly, so IMSRT-7 and IMSRT-14 can be used interchangeable. Patients with tumors contacting neither the subventricular zone nor the cortex benefit most from IMSRT (p  <  0.001). CONCLUSION: The feasibility of neural stem cell niches sparing with sophisticated linac based inverse IMSRT with 7 beamlets in an unselected cohort of intracranial tumors in relation to topographic situation has been demonstrated. Clinical relevance testing neurotoxicity remains to be demonstrated. PMID: 23883368 [PubMed - indexed for MEDLINE]
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Related Articles The anti-apoptotic and neuro-protective effects of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) on acute optic nerve injury is transient. Brain Res. 2013 Sep 26;1532:63-75 Authors: Chen M, Xiang Z, Cai J Abstract Progressive death of retinal ganglion cells (RGCs) is a major cause of irreversible visual impairment after optic nerve injury. Clinically, there are still no effective treatments for recovering the visual function at present. The probable approaches to maintain the vision and RGCs function involve in preventing RGCs from death and/or promoting the regeneration of damaged RGCs. Previous studies have shown that mesenchymal stem cells (MSCs) take neuroprotective effects on ischemia-induced cortical and spinal cord injury, however, whether MSCs have a beneficial effect on the optical nerve injury is not clearly determined. In present study, we transplanted MSCs derived from human umbilical cord blood (hUCB-MSCs) into the vitreous cavity of adult rats and investigated the probable capacity of anti-apoptosis and pro-neuroprotective effects on RGCs. RGCs were retrogradely traced by fluorescent gold particles (FG); cellular apoptosis was investigated by caspase-3 immunohistochemistry and terminal dUTP nick end labeling (TUNEL) staining. Hematoxylin-eosin (HE) staining was used to observe the morphological changes of the retina. Growth associated protein 43 (GAP-43), an established marker for axonal regeneration, was used to visualize the regenerative process over time. Expression of P2X7 receptors (P2X7R), which are responsible for inflammatory and immune responses, was also monitored in our experiments. We found that the hUCB-MSC transplantation significantly decreased cellular apoptosis and promoted the survival of RGCs in early phase. However, this protection was transient and the RGCs could not be protected from death in the end. Consistent with apoptosis detection, P2X7R was also significantly decreased in hUCB-MSC transplanted rats in the early time but without obvious difference to the rats from control group in the end. Thus, our results imply that hUCB-MSCs take anti-apoptotic, pro-neuroregenerative and anti-inflammatory effects in the early time for acute optic nerve injury in adult rats but could not prevent RGCs from death eventually. PMID: 23933426 [PubMed - indexed for MEDLINE]
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Related Articles Intravitreal transplantation of human umbilical cord blood stem cells protects rats from traumatic optic neuropathy. PLoS One. 2013;8(8):e69938 Authors: Jiang B, Zhang P, Zhou D, Zhang J, Xu X, Tang L Abstract OBJECTIVES: To treat traumatic optic neuropathy (TON) with transplantation of human umbilical cord blood stem cells (hUCBSC) and explore how transplanted stem cells participate in the neuron repairing process. METHODS: A total of 195 Sprague-Dawley rats were randomly assigned to three groups: sham-surgery, optic nerve injury, and stem cell transplant group. Optic nerve injury was established in rats by directly clamping the optic nerve for 30 seconds. hUCBSC was microinjected into the vitreous cavity of injured rats. Optic nerve function was evaluated by flash visual evoked potentials (F-VEP). Apoptosis in retina tissues was detected by TUNEL staining. GRP78 and CHOP gene expression was measured by RT-PCR. RESULTS: After injury, transplantation of hUCBSC significantly blunted a reduction in optic nerve function indicated by smaller decreases in amplitude and smaller increases in peak latency of F-VEP waveform compared to the injury alone group. Also, significant more in retinal ganglion cell (RGC) count and less in RGC apoptosis were detected after transplantation compared to injured rats. The protective effect correlated with upregulated GRP78 and downregulated CHOP mRNA expression. CONCLUSION: Intravitreal transplantation of hUCBSCs significantly blunted a reduction in optic nerve function through increasing RGC survival and decreasing retinal cell apoptosis. The protective role of transplantation was associated with upregulation of GRP78 expression and downregulation of CHOP expression in retinal cells. PMID: 23940534 [PubMed - indexed for MEDLINE]
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Related Articles Atoh7 promotes the differentiation of retinal stem cells derived from Müller cells into retinal ganglion cells by inhibiting Notch signaling. Stem Cell Res Ther. 2013;4(4):94 Authors: Song WT, Zhang XY, Xia XB Abstract INTRODUCTION: Retinal Müller cells exhibit the characteristics of retinal progenitor cells, and differentiate into ganglion cells under certain conditions. However, the number of ganglion cells differentiated from retinal Müller cells falls far short of therapeutic needs. This study aimed to develop a novel protocol to promote the differentiation of retinal Müller cells into ganglion cells and explore the underlying signaling mechanisms. METHODS: Müller cells were isolated and purified from rat retina and induced to dedifferentiate into retinal stem cells. Next the stem cells were transfected with lentivirus PGC-FU-GFP or lentivirus PGC-FU-Atoh7-GFP. In addition, the stem cells were transfected with Brn-3b siRNA or Isl-1 siRNA or treated with Notch inhibitor gamma-secretase inhibitor (GSI). RESULTS: The proportion of ganglion cells differentiated from Atoh7-tranfected stem cells was significantly higher than that of controls. Knockdown of Brn-3b or Isl-1 inhibited, while GSI promoted, the differentiation into retinal ganglion cells. Atoh7 promoted the expression of Brn-3b and Isl-1 but inhibited the expression of Notch1. CONCLUSIONS: Atoh7 promotes the differentiation of Müller cells-derived retinal stem cells into retinal ganglion cells by inhibiting Notch signaling, thus opening up a new avenue for gene therapy and optic nerve regeneration in glaucoma. PMID: 23945288 [PubMed - in process]
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Related Articles Engrafted human induced pluripotent stem cell-derived anterior specified neural progenitors protect the rat crushed optic nerve. PLoS One. 2013;8(8):e71855 Authors: Satarian L, Javan M, Kiani S, Hajikaram M, Mirnajafi-Zadeh J, Baharvand H Abstract BACKGROUND: Degeneration of retinal ganglion cells (RGCs) is a common occurrence in several eye diseases. This study examined the functional improvement and protection of host RGCs in addition to the survival, integration and neuronal differentiation capabilities of anterior specified neural progenitors (NPs) following intravitreal transplantation. METHODOLOGY/PRINCIPAL FINDINGS: NPs were produced under defined conditions from human induced pluripotent stem cells (hiPSCs) and transplanted into rats whose optic nerves have been crushed (ONC). hiPSCs were induced to differentiate into anterior specified NPs by the use of Noggin and retinoic acid. The hiPSC-NPs were labeled by green fluorescent protein or a fluorescent tracer 1,1' -dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) and injected two days after induction of ONC in hooded rats. Functional analysis according to visual evoked potential recordings showed significant amplitude recovery in animals transplanted with hiPSC-NPs. Retrograde labeling by an intra-collicular DiI injection showed significantly higher numbers of RGCs and spared axons in ONC rats treated with hiPSC-NPs or their conditioned medium (CM). The analysis of CM of hiPSC-NPs showed the secretion of ciliary neurotrophic factor, basic fibroblast growth factor, and insulin-like growth factor. Optic nerve of cell transplanted groups also had increased GAP43 immunoreactivity and myelin staining by FluoroMyelin™ which imply for protection of axons and myelin. At 60 days post-transplantation hiPSC-NPs were integrated into the ganglion cell layer of the retina and expressed neuronal markers. CONCLUSIONS/SIGNIFICANCE: The transplantation of anterior specified NPs may improve optic nerve injury through neuroprotection and differentiation into neuronal lineages. These NPs possibly provide a promising new therapeutic approach for traumatic optic nerve injuries and loss of RGCs caused by other diseases. PMID: 23977164 [PubMed - indexed for MEDLINE]
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Related Articles A regenerative approach to the treatment of multiple sclerosis. Nature. 2013 Oct 17;502(7471):327-32 Authors: Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ, Padmanabhan K, Swoboda JG, Ahmad I, Kondo T, Gage FH, Theofilopoulos AN, Lawson BR, Schultz PG, Lairson LL Abstract Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches. PMID: 24107995 [PubMed - indexed for MEDLINE]
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Related Articles [Visual function of seven children with malignant osteopetrosis after hematopoietic stem cell transplantation]. Zhonghua Yan Ke Za Zhi. 2013 Jun;49(6):541-6 Authors: Cao WH, Yu G, Qin MQ, Wu Q, Fan YW, Cui YH, Zhang CY, Shi W Abstract OBJECTIVE: To detect long-term ocular alteration of children with malignant osteopetrosis after hematopoietic stem cell transplantation. METHODS: Children diagnosed as osteopetrosis from 5 months to 31 months underwent hematopoietic stem cell transplantation. Computed tomography of optic canal, FVEP, ERG and fundus examination were applied to assess the visual function. RESULTS: Bone marrow transplantation was successful. Peripheral blood test, splenohepatomegalia and osteosclerosis improved gradually. The mean optic canal diameters of right eyes before transplantation was (1.7 ± 0.4)mm. The mean optic canal diameters of right eyes was (3.2 ± 0.7)mm after transplantation. The mean optic canal diameters of left eyes before transplantation was (1.9 ± 0.5)mm . The mean optic canal diameters of left eyes was (3.1 ± 0.8)mm after transplantation. The difference between above two groups was statistically significant(t = -5.204, -4.211;P < 0.05). P2 latency period of FVEP prolonged in 7 cases before transplantation. Mean P2 latency period of FVEP decreased 21.13 ms in 5 cases after transplantation. Mean P2 latency period of FVEP prolonged 22.25 ms in 2 cases after transplantation. Under light adaptation and dark adaptation, ERG amplitude depressed obviously in 2 cases. Two cases with optic nerve atrophy did not change after transplantation. CONCLUSIONS: Hematopoietic stem cell transplantation is an effective way to deal with malignant osteopetrosis. Successful transplantation has been shown to arrest visual deterioration in some cases. PMID: 24119969 [PubMed - indexed for MEDLINE]
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Related Articles Intravitreally transplanted dental pulp stem cells promote neuroprotection and axon regeneration of retinal ganglion cells after optic nerve injury. Invest Ophthalmol Vis Sci. 2013 Nov;54(12):7544-56 Authors: Mead B, Logan A, Berry M, Leadbeater W, Scheven BA Abstract PURPOSE: To investigate the potential therapeutic benefit of intravitreally implanted dental pulp stem cells (DPSCs) on axotomized adult rat retinal ganglion cells (RGCs) using in vitro and in vivo neural injury models. METHODS: Conditioned media collected from cultured rat DPSCs and bone marrow-derived mesenchymal stem cells (BMSCs) were assayed for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) secretion using ELISA. DPSCs or BMSCs were cocultured with retinal cells, with or without Fc-TrK inhibitors, in a Transwell system, and the number of surviving βIII-tubulin⁺ retinal cells and length/number of βIII-tubulin⁺ neurites were quantified. For the in vivo study, DPSCs or BMSCs were transplanted into the vitreous body of the eye after a surgically induced optic nerve crush injury. At 7, 14, and 21 days postlesion (dpl), optical coherence tomography (OCT) was used to measure the retinal nerve fiber layer thickness as a measure of axonal atrophy. At 21 dpl, numbers of Brn-3a⁺ RGCs in parasagittal retinal sections and growth-associated protein-43⁺ axons in longitudinal optic nerve sections were quantified as measures of RGC survival and axon regeneration, respectively. RESULTS: Both DPSCs and BMSCs secreted NGF, BDNF, and NT-3, with DPSCs secreting significantly higher titers of NGF and BDNF than BMSCs. DPSCs, and to a lesser extent BMSCs, promoted statistically significant survival and neuritogenesis/axogenesis of βIII-tubulin⁺ retinal cells in vitro and in vivo where the effects were abolished after TrK receptor blockade. CONCLUSIONS: Intravitreal transplants of DPSCs promoted significant neurotrophin-mediated RGC survival and axon regeneration after optic nerve injury. PMID: 24150755 [PubMed - indexed for MEDLINE]
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Related Articles Failure of stem cell therapy to improve visual acuity in children with optic nerve hypoplasia. J AAPOS. 2013 Oct;17(5):490-3 Authors: Fink C, Garcia-Filion P, Borchert M Abstract PURPOSE: To evaluate the effectiveness of stem cell therapy in improving visual acuity or optic nerve function in children with optic nerve hypoplasia (ONH). METHODS: Subjects with ONH aged 7-17 years who voluntarily elected to undergo stem cell therapy in China were matched with controls on age, visual acuity, and communication level. Visual acuity, optic nerve size, and sensitivity to light were assessed before stem cell therapy and twice after. Controls were evaluated on the same schedule. RESULTS: Two case-control pairs were enrolled. There were no clinically significant changes in pupillary constriction or optic nerve measurements in any participant eye. Improvement in visual acuity was noted in study participants regardless of treatment status. CONCLUSIONS: On the basis of this small sample, there is no evidence that stem cell therapy improves visual acuity in children with ONH. PMID: 24160969 [PubMed - indexed for MEDLINE]
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Related Articles Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor through analysis of the mesenchymal stem cell secretome. Brain. 2014 Feb;137(Pt 2):503-19 Authors: Johnson TV, DeKorver NW, Levasseur VA, Osborne A, Tassoni A, Lorber B, Heller JP, Villasmil R, Bull ND, Martin KR, Tomarev SI Abstract The development of neuroprotective strategies to attenuate retinal ganglion cell death could lead to novel therapies for chronic optic neuropathies such as glaucoma. Intravitreal transplantation of mesenchymal stem cells slows retinal ganglion cell death in models of optic nerve injury, but the mechanism of action remains unclear. Here we characterized the neuroprotective effects of mesenchymal stem cells and mesenchymal stem cell-derived factors in organotypic retinal explant culture and an in vivo model of ocular hypertensive glaucoma. Co-culture of rat and human bone marrow-derived mesenchymal stem cells with retinal explants increased retinal ganglion cell survival, after 7 days ex vivo, by ∼2-fold and was associated with reduced apoptosis and increased nerve fibre layer and inner plexiform layer thicknesses. These effects were not demonstrated by co-culture with human or mouse fibroblasts. Conditioned media from mesenchymal stem cells conferred neuroprotection, suggesting that the neuroprotection is mediated, at least partly, by secreted factors. We compared the concentrations of 29 factors in human mesenchymal stem cell and fibroblast conditioned media, and identified 11 enriched in the mesenchymal stem cell secretome. Treatment of retinal explants with a cocktail of these factors conferred retinal ganglion cell neuroprotection, with factors from the platelet-derived growth factor family being the most potent. Blockade of platelet-derived growth factor signalling with neutralizing antibody or with small molecule inhibitors of platelet-derived growth factor receptor kinase or downstream phosphatidylinositol 3 kinase eliminated retinal ganglion cell neuroprotection conferred by mesenchymal stem cell co-culture. Intravitreal injection of platelet-derived growth factor -AA or -AB led to profound optic nerve neuroprotection in vivo following experimental induction of elevated intraocular pressure. These data demonstrate that mesenchymal stem cells secrete a number of neuroprotective proteins and suggest that platelet-derived growth factor secretion in particular may play an important role in mesenchymal stem cell-mediated retinal ganglion cell neuroprotection. Furthermore, platelet-derived growth factor may represent an independent target for achieving retinal ganglion cell neuroprotection. PMID: 24176979 [PubMed - indexed for MEDLINE]
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Related Articles Overexpression of Wnt3a facilitates the proliferation and neural differentiation of neural stem cells in vitro and after transplantation into an injured rat retina. J Neurosci Res. 2014 Feb;92(2):148-61 Authors: Yang XT, Bi YY, Chen ET, Feng DF Abstract Neural stem cell-based therapy is a promising option for repair after injury. However, poor stem cell proliferation and insufficient differentiation of the stem cells into neurons are still difficult problems. The present study investigated whether transplantation of neural stem cells (NSCs) genetically modified to express Wnt3a is a promising approach to overcome these difficulties. We explored the possibility that Wnt3a might contribute to the therapeutic effect of NSC transplantation in retinal repair. The relative promotion of proliferation and neural differentiation by modified NSCs was investigated in a rat model of optic nerve crush. A recombinant lentivirus (Lenti-Wnt3a) was engineered to express Wnt3a. NSCs infected with control lentivirus (Lenti-GFP) or Lenti-Wnt3a were transplanted into the subretinal space immediately after the optic nerve crush. The proliferation and neural differentiation activity of the NSCs were assessed in vitro and in vivo. Overexpression of Wnt3a in NSCs induced activation of Wnt signaling, promoted proliferation, and directed the differentiation of the NSCs into neurons both in vitro and in vivo. Our study suggests that Wnt3a can potentiate the therapeutic benefits of NSC-based therapy in the injured retina. PMID: 24254835 [PubMed - indexed for MEDLINE]
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Related Articles Retinal repair with induced pluripotent stem cells. Transl Res. 2014 Apr;163(4):377-86 Authors: Al-Shamekh S, Goldberg JL Abstract Retinal degeneration such as age-related macular degeneration and other inherited forms, such as Stargardt's disease and retinitis pigmentosa, and optic neuropathies including glaucoma and ischemic optic neuropathy are major causes of vision loss and blindness worldwide. Damage to retinal pigment epithelial cells and photoreceptors in the former, and to retinal ganglion cell axons in the optic nerve and their cell bodies in the retina in the latter diseases lead to the eventual death of these retinal cells, and in humans there is no endogenous replacement or repair. Cell replacement therapies provide 1 avenue to restore function in these diseases, particularly in the case of retinal repair, although there are considerable issues to overcome, including the differentiation and integration of the transplanted cells. What stem cell sources could be used for such therapies? One promising source is induced pluripotent stem cells (iPSCs), which could be drawn from an individual patient needing therapy, or generated and banked from select donors. We review developing research in the use of iPSCs for retinal cell replacement therapy. PMID: 24291154 [PubMed - indexed for MEDLINE]
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Related Articles Survival and migration of pre-induced adult human peripheral blood mononuclear cells in retinal degeneration slow (rds) mice three months after subretinal transplantation. Curr Stem Cell Res Ther. 2014 Mar;9(2):124-33 Authors: Peng Y, Zhang Y, Huang B, Luo Y, Zhang M, Li K, Li W, Wen W, Tang S Abstract INTRODUCTION: Retinitis pigmentosa (RP), an inherited disease characterized by progressive loss of photoreceptors and retinal pigment epithelium, is a leading genetic cause of blindness. Cell transplantation to replace lost photoreceptors is a potential therapeutic strategy, but technical limitations have prevented clinical application. Adult human peripheral blood mononuclear cells (hPBMCs) may be an ideal cell source for such therapies. This study examined the survival and migration of pre-induced hPBMCs three months after subretinal transplantation in the retinal degeneration slow (rds) mouse model of RP. MATERIALS AND METHODS: Freshly isolated adult hPBMCs were pre-induced by co-culture with neonatal Sprague-Dawley (SD) rat retinal tissue for 4 days in neural stem cell medium. Pre-induced cells were labeled with CMDiI for tracing and injected into the right subretinal space of rds mice by the trans-scleral approach. After two and three months, right eyes were harvested and transplanted cell survival and migration examined in frozen sections and wholemount retinas. Immunofluorescence in whole-mount retinas was used to detect the expression of human neuronal and photoreceptors protein markers by transplanted cells. RESULTS: Pre-induced adult hPBMCs could survive in vivo and migrate to various parts of the retina. After two and three months, transplanted cells were observed in the ciliary body, retinal outer nuclear layer, inner nuclear layer, ganglion cell layer, optic papilla, and within the optic nerve. The neuronal and photoreceptor markers CD90/Thy1, MAP-2, nestin, and rhodopsin were expressed by subpopulations of CM-DiI-positive cells three months after subretinal transplantation. CONCLUSION: Pre-induced adult hPBMCs survived for at least three months after subretinal transplantation, migrated throughout the retina, and expressed human protein markers. These results suggest that hPBMCs could be used for cell replacement therapy to treat retinal degenerative diseases. PMID: 24350910 [PubMed - indexed for MEDLINE]
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Related Articles Effect of coadministration of neuronal growth factors on neuroglial differentiation of bone marrow-derived stem cells in the ischemic retina. Invest Ophthalmol Vis Sci. 2014 Jan;55(1):502-12 Authors: Goldenberg-Cohen N, Avraham-Lubin BC, Sadikov T, Askenasy N Abstract PURPOSE: Brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) have limited and transient supportive effects on retinal recovery from ischemia. The aim of this study was to investigate their effect on engrafted adult bone marrow-derived stem cells in a rodent model of anterior ischemic optic neuropathy (rAION). METHODS: Small cells were isolated from the bone marrow of green fluorescent protein expressing mice by counterflow centrifugal elutriation, depleted of cells expressing lineage markers, and grafted in conjunction with growth factors into the vitreous body of mice with unilateral rAION. Progenitors were mobilized with granulocyte macrophage colony-stimulating factor (GM-CSF) or stem cell factor (SCF). The contralateral eye served as a control. RESULTS: At 4 weeks, the quantitative incorporation of donor cells in the injured retina was increased by BDNF (P < 0.01 versus control) and decreased by CNTF (P < 0.01 versus control), with no notable difference at 24 weeks. Both growth factors improved the short-term and long-term qualitative engraftment of cells adopting neural phenotypes in the retinal ganglion cell (RGC) layer and astrocyte phenotypes in the anterior vasculature. The RGC-engrafted cells formed extensions toward the inner nuclear layer. In the presence of growth factors, donor cells migrated to the optic nerve and contributed to repair by gliosis. Mobilization with GM-CSF restricted cell fate to microglia, whereas SCF was associated with limited neuroglial differentiation. CONCLUSIONS: Both BDNF and CNTF enhance engraftment and neuroglial differentiation of adult bone marrow stem cells in injured retina, with BDNF having an early quantitative and qualitative advantage over CNTF. Mobilization with differentiation factors restricts cell fate in the injured retina. PMID: 24370836 [PubMed - indexed for MEDLINE]
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Related Articles Effect of RSCs combined with COP-1 on optic nerve damage in glaucoma rat model. Asian Pac J Trop Med. 2014 Apr;7(4):317-20 Authors: Fu WC, Jiang Y, Zhang L Abstract OBJECTIVE: To explore effect of retinal stem cells (RSCs) combined with copolymer-1 (COP-1) immunotherapy on optic nerve damage in glaucoma rat model. METHODS: A total of 40 SD rats were selected for glaucoma model and were randomly divided into 4 groups to observe protective effects of RSCs transplantation combined with COP-1. RESULTS: Brain-derived neurotrophic factor (BDNF) and insulin like growth factor-1 (IGF-1) were either positive in retina of RSCs transplanted or COP-1 immunological treated rat. Positive rate of BDNF and IGF-1 and expression of mRNA and protein were significantly higher in RSCs transplantation combined with COP-1 immunotherapy treated rats compared with the other 3 groups, in which amount of apoptotic RGCs was lowest. CONCLUSIONS: RSCs transplantation combined with COP-1 immunotherapy can promote the secretion of BDNF and IGF-1. They protect RGCs in glaucoma rats in coordination, significantly reduce the number of apoptosis RGCs so as to alleviate the optic nerve damage. It ponits a new research direction for treatment of glaucoma. PMID: 24507684 [PubMed - in process]
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Related Articles Cell therapy using retinal progenitor cells shows therapeutic effect in a chemically-induced rotenone mouse model of Leber hereditary optic neuropathy. Eur J Hum Genet. 2014 Feb 26; Authors: Mansergh FC, Chadderton N, Kenna PF, Gobbo OL, Farrar GJ Abstract Primary mitochondrial disorders occur at a prevalence of one in 10 000; ∼50% of these demonstrate ocular pathology. Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial disorder. LHON results from retinal ganglion cell pathology, which leads to optic nerve degeneration and blindness. Over 95% of cases result from one of the three common mutations in mitochondrial genes MTND1, MTND4 and MTND6, which encode elements of the complex I respiratory chain. Various therapies for LHON are in development, for example, intravitreal injection of adeno-associated virus carrying either the yeast NDI1 gene or a specific subunit of mammalian Complex I have shown visual improvement in animal models. Given the course of LHON, it is likely that in many cases prompt administration may be necessary before widespread cell death. An alternative approach for therapy may be the use of stem cells to protect visual function; this has been evaluated by us in a rotenone-induced model of LHON. Freshly dissected embryonic retinal cells do not integrate into the ganglion cell layer (GCL), unlike similarly obtained photoreceptor precursors. However, cultured retinal progenitor cells can integrate in close proximity to the GCL, and act to preserve retinal function as assessed by manganese-enhanced magnetic resonance imaging, optokinetic responses and ganglion cell counts. Cell therapies for LHON therefore represent a promising therapeutic approach, and may be of particular utility in treating more advanced disease.European Journal of Human Genetics advance online publication, 26 February 2014; doi:10.1038/ejhg.2014.26. PMID: 24569607 [PubMed - as supplied by publisher]
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Related Articles [Treatment of retinoblastoma: Senegalese experience]. J Fr Ophtalmol. 2014 May;37(5):381-7 Authors: Sow AS, Ndoye Roth PA, Moreira C, Diagne Akonde FB, Ka AM, Ndiaye Sow MN, Ba EA, Wane Khouma AM, Ndiaye MR Abstract INTRODUCTION: Retinoblastoma is a malignant tumor arising from retinal stem cells or retinoblasts. Its management has been well determined. The goal of this study is to report preliminary results obtained with combined chemotherapy and surgical treatment. PATIENTS AND METHODS: Our transverse prospective study includes retinoblastomas diagnosed and treated on our service from January 2006 to December 2010. Fundus examination under general anesthesia and radiological examination, orbital/brain CT or if unavailable, ultrasound, were systematically performed. MRI was able to be obtained in one case. The patients received 6 courses of chemotherapy (vincristin-carboplatin-etoposide or vincristin-cyclophosphamide), including 2 preoperative courses and 4 postoperative courses. A surgical procedure (enucleation or exenteration) supplemented the treatment, followed by histologic analysis of the specimen. External radiation therapy and conservative management were not available. RESULTS: Fifty-nine patients were treated. Median age at time of diagnosis was 9months (range 2months to 7years); the gender ratio was 1.18. Tumors were bilateral in 12 cases and unilateral in 47 cases, intraocular in 34 cases and extraocular in 25 cases. Optic nerve involvement was confirmed by histology in 12 cases. Twenty-one patients died from recurrence and/or metastatic disease, or during chemotherapy. Seven were lost to follow-up, and 31 have survived uneventfully. DISCUSSION: Improvement of mortality is still our major concern. Radiation therapy is essential in the presence of optic nerve involvement. CONCLUSION: Long-term survival will determine the efficacy of this form of management. The contribution of new therapeutic means will improve these results. PMID: 24679452 [PubMed - in process]
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Related Articles Regulation of intrinsic axon growth ability at retinal ganglion cell growth cones. Invest Ophthalmol Vis Sci. 2014 Jul;55(7):4369-77 Authors: Steketee MB, Oboudiyat C, Daneman R, Trakhtenberg E, Lamoureux P, Weinstein JE, Heidemann S, Barres BA, Goldberg JL Abstract PURPOSE: Mammalian central nervous system neurons fail to regenerate after injury or disease, in part due to a progressive loss in intrinsic axon growth ability after birth. Whether lost axon growth ability is due to limited growth resources or to changes in the axonal growth cone is unknown. METHODS: Static and time-lapse images of purified retinal ganglion cells (RGCs) were analyzed for axon growth rate and growth cone morphology and dynamics without treatment and after manipulating Kruppel-like transcription factor (KLF) expression or applying mechanical tension. RESULTS: Retinal ganglion cells undergo a developmental switch in growth cone dynamics that mirrors the decline in postnatal axon growth rates, with increased filopodial adhesion and decreased lamellar protrusion area in postnatal axonal growth cones. Moreover, expressing growth-suppressive KLF4 or growth-enhancing KLF6 transcription factors elicits similar changes in postnatal growth cones that correlate with axon growth rates. Postnatal RGC axon growth rate is not limited by an inability to achieve axon growth rates similar to embryonic RGCs; indeed, postnatal axons support elongation rates up to 100-fold faster than postnatal axonal growth rates. Rather, the intrinsic capacity for rapid axon growth is due to both growth cone pausing and retraction, as well as to a slightly decreased ability to achieve rapid instantaneous rates of forward progression. Finally, we observed that RGC axon and dendrite growth are regulated independently in vitro. CONCLUSIONS: Together, these data support the hypothesis that intrinsic axon growth rate is regulated by an axon-specific growth program that differentially regulates growth cone motility. PMID: 24906860 [PubMed - indexed for MEDLINE]
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Related Articles Atoh7 promotes retinal Müller cell differentiation into retinal ganglion cells. Cytotechnology. 2014 Aug 10; Authors: Song WT, Zeng Q, Xia XB, Xia K, Pan Q Abstract Glaucoma is one of the leading eye diseases due to the death of retinal ganglion cells. Increasing evidence suggests that retinal Müller cells exhibit the characteristics of retinal progenitor cells and can differentiate to neurons in injured retinas under certain conditions. However, the number of ganglion cells differentiated from retinal Müller cells falls far short of therapeutic needs. This study aimed to promote the differentiation of retinal Müller cells into ganglion cells by introducing Atoh7 into the stem cells dedifferentiated from retinal Müller cells. Rat retinal Müller cells were isolated and dedifferentiated into stem cells, which were transfected with PEGFP-N1 or PEGFP-N1-Atoh7 vector, and then further induced to differentiate into ganglion cells. The proportion of ganglion cells differentiated from Atoh7-tranfected stem cells was significantly higher than that of control transfected or untransfected cells. In summary, Atoh7 promotes the differentiation of retinal Müller cells into retinal ganglion cells. This may open a new avenue for gene therapy of glaucoma by promoting optic nerve regeneration. PMID: 25108422 [PubMed - as supplied by publisher]
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Related Articles Retinal Ganglion Cell Polarization Using Immobilized Guidance Cues on a Tissue-Engineered Scaffold. Acta Biomater. 2014 Sep 3; Authors: Kador KE, Alsehli HS, Zindell AN, Lau LW, Andreopoulos FM, Watson BD, Goldberg JL Abstract Cell transplantation therapies to treat diseases related to dysfunction of retinal ganglion cells (RGCs) are limited in part by an inability to navigate to the optic nerve head within the retina. During development, RGCs are guided by a series of neurotrophic factors and guidance cues; however, these factors and their receptors on the RGCs are developmentally regulated and often not expressed during adulthood. Netrin-1 is a guidance factor capable of guiding RGCs in culture and relevant to guiding RGC axons toward the optic nerve head in vivo. Here we immobilized Netrin-1 using UV-initiated crosslinking to form a gradient capable of guiding the axonal growth of RGCs on a radial electrospun scaffold. Netrin-gradient scaffolds promoted both the percentage of RGCs polarized with a single axon, and also the percentage of cells polarized toward the scaffold center, from 31% to 52%. Thus, an immobilized protein gradient on a radial electrospun scaffold increases RGC axon growth in a direction consistent with developmental optic nerve head guidance, and may prove beneficial for use in cell transplant therapies for the treatment of glaucoma and other optic neuropathies. PMID: 25194930 [PubMed - as supplied by publisher]
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A Laser-Induced Mouse Model with Long-Term Intraocular Pressure Elevation. PLoS One. 2014;9(9):e107446 Authors: Yun H, Lathrop KL, Yang E, Sun M, Kagemann L, Fu V, Stolz DB, Schuman JS, Du Y Abstract PURPOSE: To develop and characterize a mouse model with intraocular pressure (IOP) elevation after laser photocoagulation on the trabecular meshwork (TM), which may serve as a model to investigate the potential of stem cell-based therapies for glaucoma. METHODS: IOP was measured in 281 adult C57BL/6 mice to determine normal IOP range. IOP elevation was induced unilaterally in 50 adult mice, by targeting the TM through the limbus with a 532-nm diode laser. IOP was measured up to 24 weeks post-treatment. The optic nerve damage was detected by electroretinography and assessed by semiautomatic counting of optic nerve axons. Effects of laser treatment on the TM were evaluated by histology, immunofluorescence staining, optical coherence tomography (OCT) and transmission electron microscopy (TEM). RESULTS: The average IOP of C57BL/6 mice was 14.5±2.6 mmHg (Mean ±SD). After laser treatment, IOP averaged above 20 mmHg throughout the follow-up period of 24 weeks. At 24 weeks, 57% of treated eyes had elevated IOP with the mean IOP of 22.5±2.5 mmHg (Mean ±SED). The difference of average axon count (59.0%) between laser treated and untreated eyes was statistically significant. Photopic negative response (PhNR) by electroretinography was significantly decreased. CD45+ inflammatory cells invaded the TM within 1 week. The expression of SPARC was increased in the TM from 1 to 12 weeks. Histology showed the anterior chamber angle open after laser treatment. OCT indicated that most of the eyes with laser treatment had no synechia in the anterior chamber angles. TEM demonstrated disorganized and compacted extracellular matrix in the TM. CONCLUSIONS: An experimental murine ocular hypertension model with an open angle and optic nerve axon loss was produced with laser photocoagulation, which could be used to investigate stem cell-based therapies for restoration of the outflow pathway integrity for ocular hypertension or glaucoma. PMID: 25216052 [PubMed - as supplied by publisher]
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