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

Haibin Tian; Zhiyang Chen; Xiaoman Zhu; Qingjian Ou; Zhe Wang; Binxin Wu; Jing-Ying Xu; Caixia Jin; Furong Gao; Juan Wang; Jingfa Zhang; Jieping Zhang; Lixia Lu; Guo-Tong Xu

doi:10.1016/j.isci.2022.105050

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

iScience. 2022 Sep 2;25(10):105050. doi: 10.1016/j.isci.2022.105050. eCollection 2022 Oct 21.

Authors

Haibin Tian¹, Zhiyang Chen¹, Xiaoman Zhu¹, Qingjian Ou¹, Zhe Wang¹, Binxin Wu¹, Jing-Ying Xu¹, Caixia Jin¹, Furong Gao¹, Juan Wang¹, Jingfa Zhang², Jieping Zhang¹, Lixia Lu¹, Guo-Tong Xu^{1

3

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Affiliations

¹ Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai 200065, China.
² Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai 200080, China.
³ Department of Physiology and Pharmacology, Tongji University School of Medicine, Shanghai 200092, China.
⁴ The collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China.

Abstract

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.

Keywords: Biological sciences; Molecular biology; Stem cells research.