Sphere-induced reprogramming of RPE cells into dual-potential RPE stem-like cells

被引：16

作者：

Chen, Fenghua ^{[1
,4
]}

Liu, Xiao ^{[1
,5
]}

Chen, Yao ^{[1
,6
]}

Liu, John Y. ^{[1
]}

Lu, Huayi ^{[1
,7
]}

Wang, Wei ^{[1
]}

Lu, Xiaoqin ^{[1
]}

Dean, Kevin C. ^{[1
]}

Gao, Ling ^{[5
]}

Kaplan, Henry J. ^{[1
]}

Dean, Douglas C. ^{[1
,2
,3
]}

Peng, Xiaoyan ^{[4
]}

Liu, Yongqing ^{[1
,2
,3
]}

机构：

[1] Univ Louisville, Dept Ophthalmol & Visual Sci, Sch Med, 301 E Muhammad Ali Blvd, Louisville, KY 40202 USA

[2] Univ Louisville, James Graham Brown Canc Ctr, Sch Med, Louisville, KY 40202 USA

[3] Univ Louisville, Birth Defects Ctr, Sch Med, Louisville, KY 40202 USA

[4] Capital Med Univ, Beijing Tongren Hosp, Dept Ophthalmol, Beijing 100005, Peoples R China

[5] Cent South Univ, Xiangya Med Sch, Dept Ophthalmol, Affiliated Hosp 2, Changsha, Peoples R China

[6] Cent South Univ, Xiangya Hosp, Dept Ophthalmol, Changsha, Peoples R China

[7] Jilin Univ, Hosp 2, Changchun, Jilin, Peoples R China

来源：

EBIOMEDICINE | 2020年 / 52卷

基金：

中国国家自然科学基金;

关键词：

RPE stem cells; Sphere-induced reprogramming; Retina degeneration; Cell transplantation; EPITHELIAL-MESENCHYMAL TRANSITION; RETINAL-PIGMENT EPITHELIUM; VISUAL FUNCTION; HIPPO PATHWAY; MULLER GLIA; ZEB1; PROLIFERATION; ORGANOIDS; MODEL; DIFFERENTIATION;

D O I：

10.1016/j.ebiom.2019.102618

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. (C) 2019 The Author(s). Published by Elsevier B.V.

引用

页数：12

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