The long-term goal of this project is to produce new photoreceptors for cell replacement. Photoreceptor replacement holds great promise in treating visual impairments caused by photoreceptor degeneration. At the same time, it presents the need for a supply of differentiating photoreceptors, because the human neural retina lacks regeneration capability. To address this critical barrier in developing photoreceptor-replacement therapies, we take a rather unconventional approach to generate differentiating photoreceptors - reprogramming RPE cells with a pro-photoreceptor gene to channel RPE's well-known capabilities of proliferation and plasticity towards photoreceptor production. Studies with chick cells raise the exciting possibility of deriving new photoreceptors from the RPE through gene-directed reprogramming. Interesting as it stands, it is time to test the hypothesis that mammalian RPE cells can be reprogrammed to give rise to photoreceptor cells. Validation of the hypothesis bears clinical and societal significance. To test the hypothesis, we designed two sets of complementary studies. The first set directly examines cultured human RPE cells for their capacity to produce photoreceptor cells under the guidance of a pro-photoreceptor gene ngn1. Human RPE cells will be virally transduced with ngn1 to initiate photoreceptor differentiation. The cell culture will then be analyzed for de novo production of photoreceptor-like neurons at the levels of gene expression, cellular morphology, and functional physiology, in vitro and in vivo after transplantation into the eyes. A direct test with human cells bears high relevance to the development of potential therapy. The second set investigates whether new photoreceptor cells will be generated from the mouse RPE ectopically expressing pro-photoreceptor gene ngn1. Ectopic ngn1 expression in the RPE will be achieved using viral delivery and transgenics. The ngn1-RPE will then be subjected to conditions, such as the in vivo environment of photoreceptor degeneration, that may unleash the experimental RPE's potential to give rise to photoreceptor cells. This will be followed by analyses for de novo generation of photoreceptor cells at molecular, cellular, and physiological levels. In addition to testing our hypothesis, a demonstration of """"""""RPE ->photoreceptor"""""""" reprogramming in mice will provide scientific evidence for future investigation into RPE as a convenient source of photoreceptors for in situ cell replacement without cell transplantation. Together, the studies promise information vital to using the RPE to repopulate the retina afflicted with photoreceptor degeneration.

Public Health Relevance

A critical barrier to progress in developing photoreceptor replacement therapy is a lack of reliable source of new photoreceptors. This project investigates gene-directed reprogramming of RPE cells as a novel approach to produce new photoreceptors for future cell replacement studies.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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University of Alabama Birmingham
Schools of Medicine
United States
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Yan, Run-Tao; He, Li; Zhan, Wenjie et al. (2015) Induction of ectopic retina-like tissue by transgenic expression of neurogenin. PLoS One 10:e0116171
Wang, Shu-Zhen; Yan, Run-Tao (2014) The Retinal Pigment Epithelium: a Convenient Source of New Photoreceptor cells? J Ophthalmic Vis Res 9:83-93
Yan, Run-Tao; Li, Xiumei; Wang, Shu-Zhen (2013) Photoreceptor-like cells in transgenic mouse eye. Invest Ophthalmol Vis Sci 54:4766-75
Yan, Run-Tao; Li, Xiumei; Huang, Jian et al. (2013) Photoreceptor-like cells from reprogramming cultured mammalian RPE cells. Mol Vis 19:1178-87
Ma, Wenxin; Wang, Shu-Zhen (2012) Fate tracing of neurogenin2-expressing cells in the mouse retina using CreERýýý: LacZ. Methods Mol Biol 884:141-52
Wang, Shu-Zhen; Yan, Run-Tao (2012) Chick retinal pigment epithelium transdifferentiation assay for proneural activities. Methods Mol Biol 884:201-9
Yan, Run-Tao; Wang, Shu-Zhen (2012) Production of high-titer RCAS retrovirus. Methods Mol Biol 884:193-9
Li, Xiumei; Ma, Wenxin; Zhuo, Yehong et al. (2010) Using neurogenin to reprogram chick RPE to produce photoreceptor-like neurons. Invest Ophthalmol Vis Sci 51:516-25
Wang, Shu-Zhen; Ma, Wenxin; Yan, Run-Tao et al. (2010) Generating retinal neurons by reprogramming retinal pigment epithelial cells. Expert Opin Biol Ther 10:1227-39
Yan, Run-Tao; Liang, Lina; Ma, Wenxin et al. (2010) Neurogenin1 effectively reprograms cultured chick retinal pigment epithelial cells to differentiate toward photoreceptors. J Comp Neurol 518:526-46

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