Sphere-induced Reprogramming of RPE Cells into Dual-potential RPE Stem-like Cells

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2020 Jan 27

PMID 31982829

Citations 10

Authors

Fenghua Chen

Xiao Liu

Yao Chen

John Y Liu

Huayi Lu

Wei Wang

Xiaoqin Lu

Kevin C Dean

Ling Gao

Henry J Kaplan

Douglas C Dean

Xiaoyan Peng

Yongqing Liu

Affiliations

Soon will be listed here.

Abstract

Background: The retinal pigment epithelium (RPE) has the potential to regenerate the entire neuroretina upon retinal injury in amphibians. In contrast, this regenerative capacity has been lost in mammals. The reprogramming of differentiated somatic cells into induced pluripotent stem cells (iPSCs) by viral transduction of exogenous stem cell factors has triggered a revolution in regenerative medicine. However, the risks of potential mutation(s) caused by random viral vector insertion in host genomes and tumor formation in recipients hamper its clinical application. One alternative is to immortalize adult stem cells with limited potential or to partially reprogram differentiated somatic cells into progenitor-like cells through non-integration protocols.

Methods: Sphere-induced RPE stem cells (iRPESCs) were generated from adult mouse RPE cells. Their stem cell functionality was studied in a mouse model of retinal degeneration. The molecular mechanism underlying the sphere-induced reprogramming was investigated using microarray and loss-of-function approaches.

Findings: We provide evidence that our sphere-induced reprogramming protocol can immortalize and transform mouse RPE cells into iRPESCs with dual potential to differentiate into cells that express either RPE or photoreceptor markers both in vitro and in vivo. When subretinally transplanted into mice with retinal degeneration, iRPESCs can integrate to the RPE and neuroretina, thereby delaying retinal degeneration in the model animals. Our molecular analyses indicate that the Hippo signaling pathway is important in iRPESC reprogramming.

Interpretation: The Hippo factor Yap1 is activated in the nuclei of cells at the borders of spheres. The factors Zeb1 and P300 downstream of the Hippo pathway are shown to bind to the promoters of the stemness genes Oct4, Klf4 and Sox2, thereby likely transactivate them to reprogram RPE cells into iRPESCs. FUND: National Natural Science Foundation of China and the National Institute of Health USA.

Citing Articles

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Rzhanova L, Markitantova Y, Aleksandrova M Cells. 2024; 13(3.

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