Retinal Stem Cells Transplanted into Models of Late Stages of Retinitis Pigmentosa Preferentially Adopt a Glial or a Retinal Ganglion Cell Fate

Canola, Kriss; Angénieux, Brigitte; Tekaya, M.; Quiambao, Alexander B.; Naash, Muna I.; Munier, Francis L.; Schorderet, Daniel F.; Arsenijévic, Yvan

doi:10.1167/iovs.06-0190

Cited by 98 publications

(66 citation statements)

References 53 publications

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“…Retinal flat mounts from all four groups were probed with anti-NeuN (Fig. 3A), a marker for RGCs (Canola et al, 2007;Dijk et al, 2007;Zhong et al, 2007;Buckingham et al, 2008) and some displaced amacrine cells. Young mice had a high NeuNpositive cell density throughout the entire retina whereas Mice that exhibited an IOP below 13 mmHg ( · ) were not likely to have appreciable RGC loss and were not included within this study.…”

Section: Resultsmentioning

confidence: 99%

Systemic Adeno-Associated Virus-Mediated Gene Therapy Preserves Retinal Ganglion Cells and Visual Function in DBA/2J Glaucomatous Mice

et al. 2011

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A slow progressive death of neurons is the hallmark of neurodegenerative diseases, such as glaucoma. A therapeutic candidate, erythropoietin (EPO), has shown promise in many models of these diseases; however, it also causes polycythemia, a potentially lethal side effect. We have developed a novel mutant form of EPO that is neuroprotective but no longer erythropoietic by altering a single amino acid (arginine to glutamate at position 76; R76E). We hypothesized that a single intramuscular injection of recombinant adeno-associated virus carrying EpoR76E (rAAV2/5.CMV.EpoR76E) would protect retinal ganglion cells in a mouse model of glaucoma without inducing polycythemia. This systemic treatment not only protected the retinal ganglion cell somata located within the retina; it also preserved axonal projections within the optic nerve, while maintaining the hematocrit within normal limits. The rescued retinal ganglion cells retained their visual function demonstrated by flash visual evoked potentials. To our knowledge, this is the first demonstration of a therapy that protects neurons from death and prevents loss of visual function from the slow neurodegenerative effects of glaucoma. Because of its broad range of cellular targets, EpoR76E is likely to be successful in treating other neurodegenerative diseases as well.

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Section: Resultsmentioning

confidence: 99%

Systemic Adeno-Associated Virus-Mediated Gene Therapy Preserves Retinal Ganglion Cells and Visual Function in DBA/2J Glaucomatous Mice

et al. 2011

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“…NeuN is a DNA-binding protein that identifies most mature neuronal populations, and recent studies have used NeuN as a marker for RGCs in the GCL of the retina (Canola et al, 2007;Dijk et al, 2007;Zhong et al, 2007). In addition to RGCs, the GCL is comprised of a large number of displaced amacrine cells.…”

Section: Neun Can Be Used To Monitor Ganglion Cells In the Gclmentioning

confidence: 99%

“…NeuN has been used to identify neurons in the retina (Wang et al, 2000), with some groups observing NeuN expression exclusive to RGCs in the GCL (Canola et al, 2007;Dijk et al, 2007;Zhong et al, 2007). The GCL is comprised of approximately equal numbers of RGCs and displaced amacrine cells (Jeon et al, 1998), and, to date, there has not been a study that presents evidence for the unequivocal absence of NeuN in displaced amacrine cells.…”

Section: Neun-positive Rgcs Persist Through Axon Degenerationmentioning

confidence: 99%

Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Buckingham¹,

Inman²,

Lambert³

et al. 2008

J. Neurosci.

376

336

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Glaucoma is characterized by retinal ganglion cell (RGC) pathology and a progressive loss of vision. Previous studies suggest RGC death is responsible for vision loss in glaucoma, yet evidence from other neurodegenerative diseases suggests axonal degeneration, in the absence of neuronal loss, can significantly affect neuronal function. To characterize RGC degeneration in the DBA/2 mouse model of glaucoma, we quantified RGCs in mice of various ages using neuronal-specific nuclear protein (NeuN) immunolabeling, retrograde labeling, and optic nerve axon counts. Surprisingly, the number of NeuN-labeled RGCs did not decline significantly until 18 months of age, at which time a significant decrease in RGC somal size was also observed. Axon dysfunction and degeneration occurred before loss of NeuN-positive RGCs, because significant declines in RGC number assayed by retrograde tracers and axon counts were observed at 13 months. To examine whether axonal dysfunction/degeneration affected gene expression in RGC axons or somas, NeuN and neurofilament-heavy (NF-H) immunolabeling was performed along with quantitative reverse transcription-PCR for RGC-specific genes in retinas of aged DBA/2 mice. Although these mice had similar numbers of NeuN-positive RGCs, the expression of neurofilament light, Brn-3b, and Sncg mRNA varied; this variation in RGC-specific gene expression was correlated with the appearance of NF-H immunoreactive RGC axons. Together, these data support a progression of RGC degeneration in this model of glaucoma, beginning with loss of retrograde label, where axon dysfunction and degeneration precede neuronal loss. This progression of degeneration suggests a need to examine the RGC axon as a locus of pathology in glaucoma.

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“…As with RPCs, RSCs transplanted into the subretinal space of young mice survive, migrate, integrate, and differentiate into appropriate cell types, including photoreceptor cells [24]. In healthy adult recipients, however, transplanted RSCs preferentially express ganglion cell or glial markers rather than the photoreceptor cell type needed for replacement of the outer retina [25]. Furthermore, as also found with transplantation of retinal aggregates, RSCs from younger donors integrate more appropriately than those derived from older donors, and more extensive integration occurs when the host retina is injured or diseased [26,27].…”

Section: Rscsmentioning

confidence: 99%

Stem Cells for Retinal Replacement Therapy

Stern

Temple

2011

Neurotherapeutics

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Retinal degenerative disease has limited therapeutic options and the possibility of stem cell-mediated regenerative treatments is being actively explored for these blinding retinal conditions. The relative accessibility of this central nervous system tissue and the ability to visually monitor changes after transplantation make the retina and adjacent retinal pigment epithelium prime targets for pioneering stem cell therapeutics. Prior work conducted for several decades indicated the promise of cell transplantation for retinal disease, and new strategies that combine these established surgical approaches with stem cell-derived donor cells is ongoing. A variety of tissue-specific and pluripotent-derived donor cells are being advanced to replace lost or damaged retinal cells and/or to slow the disease processes by providing neuroprotective factors, with the ultimate aim of long-term improvement in visual function. Clinical trials are in the early stages, and data on safety and efficacy are widely anticipated. Positive outcomes from these stem cell-based clinical studies would radically change the way that blinding disorders are approached in the clinic.

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Retinal Stem Cells Transplanted into Models of Late Stages of Retinitis Pigmentosa Preferentially Adopt a Glial or a Retinal Ganglion Cell Fate

Cited by 98 publications

References 53 publications

Systemic Adeno-Associated Virus-Mediated Gene Therapy Preserves Retinal Ganglion Cells and Visual Function in DBA/2J Glaucomatous Mice

Systemic Adeno-Associated Virus-Mediated Gene Therapy Preserves Retinal Ganglion Cells and Visual Function in DBA/2J Glaucomatous Mice

Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Stem Cells for Retinal Replacement Therapy

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