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Daniel Feitelberg, Peter D Westenskow, Stephen Bravo, Toshihide Kurihara, Felicitas Bucher, Liliana P Paris, Edith Aguilar, Carli M Wittgrove, Jonathan H. Lin, Martin Friedlander; Human iPSC-derived retinal pigment epithelium allografts are stable for over two years and do not elicit detrimental effects in rats. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1838.
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© ARVO (1962-2015); The Authors (2016-present)
Age related macular degeneration (AMD) is the leading cause of vision loss in industrialized countries and may be caused by retinal pigment epithelium (RPE) death or dysfunction. Replacing dysfunctional RPE with induced pluripotent stem cell (iPSC) derived-RPE may represent a viable therapy, but concerns regarding persistence of iPSC-RPE, tumorigenesis potential, and immunogenicity of stem cell-derived implants have been raised. Many studies, including our own, have shown that hiPSC-RPE grafts in the subretinal space of Royal College of Surgeons (RCS) rats can slow photoreceptor degeneration. In this study we report that transplanted hiPSC-RPE cells do not elicit gross detrimental effects and remain viable and functional throughout the entire life of the animals.
Suspensions of hiPS-RPE were injected in the subretinal space of RCS rats and the animals were examined daily throughout their lives. Pathologists performed necropsies and blood tests and specific tissues were examined for any abnormalities. Primary RPE cultures were generated from a cohort of the 2+ year-old rats injected with hiPS-RPE, and flow cytometry-based phagocytosis assays and immunocytochemistry techniques were employed to determine if they were functional human RPE.
Necropsies and blood tests revealed no gross abnormalities or an increased incidence of neoplasms in rats with hiPS-RPE grafts. Immunohistochemistry revealed that the hiPSC-RPE cells that integrated successfully in the subretinal space survived as long as 2 ½ years post-injection while the non-integrating RPE were consumed by host macrophages. Implanted hiPS-RPE could be successfully isolated and maintained in culture from the 2+ year-old rats. These displayed specific human antigens and readily, phagocytosed isolated photoreceptor outer segments.
We have shown previously that iPSC-RPE grafts provide temporary photoreceptor rescue in RCS rats. In this study we performed longitudinal monitoring of the same RCS rats throughout the duration of their lives in order to determine the safety and functionality of hiPS-RPE cells over a 2 ½ year period. Although hiPS-RPE transplantation probably does not represent a cure for AMD, our findings show that hiPS-RPE grafts can provide temporary rescue and slow photoreceptor degeneration without eliciting secondary effects.
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