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      Protection of Visual Functions by Human Neural Progenitors in a Rat Model of Retinal Disease

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          Abstract

          Background

          A promising clinical application for stem and progenitor cell transplantation is in rescue therapy for degenerative diseases. This strategy seeks to preserve rather than restore host tissue function by taking advantage of unique properties often displayed by these versatile cells. In studies using different neurodegenerative disease models, transplanted human neural progenitor cells (hNPC) protected dying host neurons within both the brain and spinal cord. Based on these reports, we explored the potential of hNPC transplantation to rescue visual function in an animal model of retinal degeneration, the Royal College of Surgeons rat.

          Methodology/Principal Findings

          Animals received unilateral subretinal injections of hNPC or medium alone at an age preceding major photoreceptor loss. Principal outcomes were quantified using electroretinography, visual acuity measurements and luminance threshold recordings from the superior colliculus. At 90–100 days postnatal, a time point when untreated rats exhibit little or no retinal or visual function, hNPC-treated eyes retained substantial retinal electrical activity and visual field with near-normal visual acuity. Functional efficacy was further enhanced when hNPC were genetically engineered to secrete glial cell line-derived neurotrophic factor. Histological examination at 150 days postnatal showed hNPC had formed a nearly continuous pigmented layer between the neural retina and retinal pigment epithelium, as well as distributed within the inner retina. A concomitant preservation of host cone photoreceptors was also observed.

          Conclusions/Significance

          Wild type and genetically modified human neural progenitor cells survive for prolonged periods, migrate extensively, secrete growth factors and rescue visual functions following subretinal transplantation in the Royal College of Surgeons rat. These results underscore the potential therapeutic utility of hNPC in the treatment of retinal degenerative diseases and suggest potential mechanisms underlying their effect in vivo.

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          Most cited references 69

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          Mammalian neural stem cells.

           Brian F Gage (2000)
          Neural stem cells exist not only in the developing mammalian nervous system but also in the adult nervous system of all mammalian organisms, including humans. Neural stem cells can also be derived from more primitive embryonic stem cells. The location of the adult stem cells and the brain regions to which their progeny migrate in order to differentiate remain unresolved, although the number of viable locations is limited in the adult. The mechanisms that regulate endogenous stem cells are poorly understood. Potential uses of stem cells in repair include transplantation to repair missing cells and the activation of endogenous cells to provide "self-repair. " Before the full potential of neural stem cells can be realized, we need to learn what controls their proliferation, as well as the various pathways of differentiation available to their daughter cells.
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            The retinal pigment epithelium in visual function.

             Olaf Strauss (2005)
            Located between vessels of the choriocapillaris and light-sensitive outer segments of the photoreceptors, the retinal pigment epithelium (RPE) closely interacts with photoreceptors in the maintenance of visual function. Increasing knowledge of the multiple functions performed by the RPE improved the understanding of many diseases leading to blindness. This review summarizes the current knowledge of RPE functions and describes how failure of these functions causes loss of visual function. Mutations in genes that are expressed in the RPE can lead to photoreceptor degeneration. On the other hand, mutations in genes expressed in photoreceptors can lead to degenerations of the RPE. Thus both tissues can be regarded as a functional unit where both interacting partners depend on each other.
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              GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons.

              A potent neurotrophic factor that enhances survival of midbrain dopaminergic neurons was purified and cloned. Glial cell line-derived neurotrophic factor (GDNF) is a glycosylated, disulfide-bonded homodimer that is a distantly related member of the transforming growth factor-beta superfamily. In embryonic midbrain cultures, recombinant human GDNF promoted the survival and morphological differentiation of dopaminergic neurons and increased their high-affinity dopamine uptake. These effects were relatively specific; GDNF did not increase total neuron or astrocyte numbers nor did it increase transmitter uptake by gamma-aminobutyric-containing and serotonergic neurons. GDNF may have utility in the treatment of Parkinson's disease, which is marked by progressive degeneration of midbrain dopaminergic neurons.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS ONE
                plos
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2007
                28 March 2007
                : 2
                : 3
                Affiliations
                [1 ]Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States of America
                [2 ]Departments of Anatomy and Neurology, University of Wisconsin, Madison, Wisconsin, United States of America
                [3 ]Waisman Center Stem Cell Research Program, University of Wisconsin, Madison, Wisconsin, United States of America
                [4 ]Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, Utah, United States of America
                [5 ]Department of Ophthalmology, Casey Eye Institute, Oregon Health and Sciences University, Portland, Oregon, United States of America
                [6 ]Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada
                University of Washington (Seattle), United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: dgamm@ 123456wisc.edu

                Conceived and designed the experiments: CS YS DG SW SG RL. Performed the experiments: YS DG TH RS EC SW BL SG NB. Analyzed the data: YS DG TH RS EC SW BL SG NB RL. Contributed reagents/materials/analysis tools: CS YS DG EC SW RL. Wrote the paper: DG.

                Article
                07-PONE-RA-00576R1
                10.1371/journal.pone.0000338
                1828619
                17396165
                Gamm et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 10
                Categories
                Research Article
                Developmental Biology/Stem Cells
                Ophthalmology/Retinal Disorders
                Surgery/Transplantation

                Uncategorized

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