iScience (Oct 2022)

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

Journal volume & issue
Vol. 25, no. 10
p. 105050

Abstract

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Summary: 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.

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