Retinal Pigmented Epithelial Cells Obtained from Human Induced Pluripotent Stem Cells Possess Functional Visual Cycle Enzymes in Vitro and in Vivo |
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Authors: | Tadao Maeda Mee Jee Lee Grazyna Palczewska Stefania Marsili Paul J Tesar Krzysztof Palczewski Masayo Takahashi Akiko Maeda |
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Institution: | From the Departments of ‡Ophthalmology and Visual Sciences.;§Pharmacology, and ;‖Genetics, Case Western Reserve University, Cleveland, Ohio 44106.;¶Polgenix, Inc., Cleveland, Ohio 44106, and ;the **Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan |
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Abstract: | Differentiated retinal pigmented epithelial (RPE) cells have been obtained from human induced pluripotent stem (hiPS) cells. However, the visual (retinoid) cycle in hiPS-RPE cells has not been adequately examined. Here we determined the expression of functional visual cycle enzymes in hiPS-RPE cells compared with that of isolated wild-type mouse primary RPE (mpRPE) cells in vitro and in vivo. hiPS-RPE cells appeared morphologically similar to mpRPE cells. Notably, expression of certain visual cycle proteins was maintained during cell culture of hiPS-RPE cells, whereas expression of these same molecules rapidly decreased in mpRPE cells. Production of the visual chromophore, 11-cis-retinal, and retinosome formation also were documented in hiPS-RPE cells in vitro. When mpRPE cells with luciferase activity were transplanted into the subretinal space of mice, bioluminance intensity was preserved for >3 months. Additionally, transplantation of mpRPE into blind Lrat−/− and Rpe65−/− mice resulted in the recovery of visual function, including increased electrographic signaling and endogenous 11-cis-retinal production. Finally, when hiPS-RPE cells were transplanted into the subretinal space of Lrat−/− and Rpe65−/− mice, their vision improved as well. Moreover, histological analyses of these eyes displayed replacement of dysfunctional RPE cells by hiPS-RPE cells. Together, our results show that hiPS-RPE cells can exhibit a functional visual cycle in vitro and in vivo. These cells could provide potential treatment options for certain blinding retinal degenerative diseases. |
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Keywords: | Induced Pluripotent Stem (iPS) Cell Retinal Degeneration Retinal Metabolism Retinoid Transplantation LRAT RPE RPE65 Visual Cycle |
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