Induced retinal pigment epithelial cells with anti-epithelial-to-mesenchymal transition ability delay retinal degeneration

• Published in: iScience 2022-10, Vol.25 (10), p.105050-105050, Article 105050
• Main Authors: Tian, Haibin, Chen, Zhiyang, Zhu, Xiaoman, Ou, Qingjian, Wang, Zhe, Wu, Binxin, Xu, Jing-Ying, Jin, Caixia, Gao, Furong, Wang, Juan, Zhang, Jingfa, Zhang, Jieping, Lu, Lixia, Xu, Guo-Tong
• Format: Article
• Language: English
• Subjects: Biological sciences; Molecular biology; Stem cells research
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.105050

The hostile microenvironment of the retina in patients with age-related macular degeneration (AMD) may trigger epithelial-to-mesenchymal transition (EMT) of grafted retinal pigment epithelial (RPE) cells, thus attenuating the therapeutic outcome. Here, we transformed human dedifferentiated induced pluripotent stem cell-derived RPE (iPSC-RPE) cells into induced RPE (iRPE) cells using a cocktail of four transcription factors (TFs)—CRX, MITF-A, NR2E1, and C-MYC. These critical TFs maintained the epithelial property of iRPE cells by regulating the expression of bmp7, forkhead box f2, lin7a, and pard6b, and conferred resistance to TGF-β-induced EMT in iRPE cells by targeting ppm1a. The iRPE cells with Tet-on system-regulated c-myc expression exhibited EMT resistance and better therapeutic function compared with iPSC-RPE cells in rat AMD model. Our study demonstrates that endowing RPE cells with anti-EMT property avoids the risk of EMT after cells are grafted into the subretinal space, and it may provide a suitable candidate for AMD treatment. [Display omitted] •CRX, MITF-A, NR2E1, and C-MYC transform De-iPSC-RPE cells into iRPE cells•iRPE cells have resistance to TGF-β-induced EMT•BMP7, FOXF2, LIN7A, PARD6B, and PPM1A mediate the functions of TFs in iRPE cells•iRPE cells have better retinal protective function than iPSC-RPE cells Biological sciences; Molecular biology; Stem cells research