Retinal Pigmented Epithelial Cells Obtained from Human Induced Pluripotent Stem Cells Possess Functional Visual Cycle Enzymes in Vitro and in Vivo

• Published in: The Journal of biological chemistry Vol. 288; no. 48; pp. 34484 - 34493
• Main Authors: Maeda, Tadao, Lee, Mee Jee, Palczewska, Grazyna, Marsili, Stefania, Tesar, Paul J., Palczewski, Krzysztof, Takahashi, Masayo, Maeda, Akiko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.11.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Biology; Cell Differentiation; Cells, Cultured; cis-trans-Isomerases - deficiency; cis-trans-Isomerases - genetics; Gene Expression Regulation, Enzymologic; Humans; Induced Pluripotent Stem (iPS) Cell; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - enzymology; Induced Pluripotent Stem Cells - transplantation; LRAT; Mice; Retinal Degeneration; Retinal Degeneration - genetics; Retinal Degeneration - pathology; Retinal Degeneration - therapy; Retinal Metabolism; Retinal Pigment Epithelium - enzymology; Retinal Pigment Epithelium - transplantation; Retinaldehyde - biosynthesis; Retinaldehyde - genetics; Retinoid; RPE; RPE65; Transplantation; Vision, Ocular - genetics; Vision, Ocular - physiology; Visual Cycle; Visual Cycle; Retinal Degeneration; RPE; Retinoid; Induced Pluripotent Stem (iPS) Cell; Transplantation; LRAT; Retinal Metabolism; RPE65
• ISSN: 0021-9258; 1083-351X; 1067-8816; 1083-351X
• DOI: 10.1074/jbc.M113.518571

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. Background: The visual (retinoid) cycle activity in human iPS-derived RPE (hiPS-RPE) cells has not been fully examined. Results: hiPS-RPE cells showed a functional visual cycle in both in vitro and in vivo. Conclusion: hiPS-RPE cell could provide potential treatment options for retinal degenerative diseases. Significance: hiPS-RPE cells with functional visual cycle proteins potentially could remedy certain degenerative retinal diseases.