Vitamin C- and Valproic Acid-Induced Fetal RPE Stem-like Cells Recover Retinal Degeneration via Regulating SOX2
Vitamin C- and Valproic Acid-Induced Fetal RPE Stem-like Cells Recover Retinal Degeneration via Regulating SOX2
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维生素 C 和丙戊酸诱导的胎儿 RPE 干细胞通过调节 SOX2 恢复视网膜变性
DOI：
10.1016/j.ymthe.2020.04.008
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发表时间：
2020
影响因子：
12.4
通讯作者：
Liu Qinghuai
中科院分区：
文献类型：
--
作者：
Shen Han;Ding Chenyue;Yuan Songtao;Pan Ting;Li Duo;Li Hong;Huang Boxian;Liu Qinghuai
视网膜色素上皮（RPE）细胞替代疗法在视网膜变性疾病（RDD）的治疗中提供了有希望的结果，但由此产生的有限的视力改善提出了关于移植物存活和分化的问题。通过与维生素C和丙戊酸（合在一起，VV）的联合处理，我们激活了人胎儿RPE（fRPE）细胞，使其成为高度增殖的胎儿RPE干细胞样细胞（fRPESC）。在这项研究中，我们报告说，SOX 2（SRY-box 2）的激活有助于间充质上皮细胞转化和fRPESCs的视网膜祖细胞和间充质基质标记物的表达升高。这些fRPESC可以在限定的条件下分化成RPE细胞、视杆细胞光感受器和间充质谱系后代。最后，将fRPESC移植到RDD小鼠模型的视网膜下腔中，并证明了光感受器拯救益处。移植的fRPESCs的RPE和视杆细胞分化可能是神经视网膜恢复的原因。本研究将fRPESC确立为高度增殖的、多谱系分化潜能（包括RPE、视杆细胞感光体和间充质谱系分化）、间充质至上皮转化的视网膜干细胞样细胞来源，用于基于细胞的RDD治疗。
Retinal pigment epithelial (RPE) cell replacement therapy has provided promising outcomes in the treatment of retinal degenerative diseases (RDDs), but the resulting limited visual improvement has raised questions about graft survival and differentiation. Through combined treatment with vitamin C and valproic acid (together, VV), we activated human fetal RPE (fRPE) cells to become highly proliferative fetal RPE stem-like cells (fRPESCs). In this study, we report that SOX2 (SRY-box 2) activation contributed to mesenchymal-epithelial transition and elevated the retinal progenitor and mesenchymal stromal markers expressions of fRPESCs. These fRPESCs could differentiate into RPE cells, rod photoreceptors, and mesenchymal lineage progenies under defined conditions. Finally, fRPESCs were transplanted into the subretinal space of an RDD mouse model, and a photoreceptor rescue benefit was demonstrated. The RPE and rod photoreceptor differentiation of transplanted fRPESCs may account for the neural retinal recovery. This study establishes fRPESCs as a highly proliferative, multi-lineage differentiation potential (including RPE, rod photoreceptor, and mesenchymal lineage differentiation), mesenchymal-to-epithelial-transitioned retinal stem-like cell source for cell-based therapy of RDDs.