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.
Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai, 200080, China.
Cell Death Dis. 2022 Sep 12;13(9):785. doi: 10.1038/s41419-022-05199-5.
Age-related macular degeneration (AMD) is a major vision-threatening disease. Although mesenchymal stem cells (MSCs) exhibit beneficial neural protective effects, their limited differentiation capacity in vivo attenuates their therapeutic function. Therefore, the differentiation of MSCs into retinal pigment epithelial (RPE) cells in vitro and their subsequent transplantation into the subretinal space is expected to improve the outcome of cell therapy. Here, we transdifferentiated human umbilical cord MSCs (hUCMSCs) into induced RPE (iRPE) cells using a cocktail of five transcription factors (TFs): CRX, NR2E1, C-MYC, LHX2, and SIX6. iRPE cells exhibited RPE specific properties, including phagocytic ability, epithelial polarity, and gene expression profile. In addition, high expression of PTPN13 in iRPE cells endows them with an epithelial-to-mesenchymal transition (EMT)-resistant capacity through dephosphorylating syntenin1, and subsequently promoting the internalization and degradation of transforming growth factor-β receptors. After grafting into the subretinal space of the sodium iodate-induced rat AMD model, iRPE cells demonstrated a better therapeutic function than hUCMSCs. These results suggest that hUCMSC-derived iRPE cells may be promising candidates to reverse AMD pathophysiology.
年龄相关性黄斑变性（AMD）是一种主要的致盲性疾病。间充质干细胞（MSCs）虽具有有益的神经保护作用，但在体内的分化能力有限，减弱了其治疗功能。因此，将 MSCs 在体外分化为视网膜色素上皮（RPE）细胞，并随后将其移植到视网膜下腔，有望改善细胞治疗的效果。在这里，我们使用 5 种转录因子（TFs）的鸡尾酒（CRX、NR2E1、C-MYC、LHX2 和 SIX6）将人脐带间充质干细胞（hUCMSCs）转分化为诱导的 RPE（iRPE）细胞。iRPE 细胞表现出 RPE 特有的特性，包括吞噬能力、上皮极性和基因表达谱。此外，iRPE 细胞中 PTPN13 的高表达通过去磷酸化 syntenin1 赋予其 EMT 抵抗能力，随后促进转化生长因子-β受体的内化和降解。将 iRPE 细胞移植到碘酸钠诱导的大鼠 AMD 模型的视网膜下腔后，其治疗功能优于 hUCMSCs。这些结果表明，hUCMSC 来源的 iRPE 细胞可能是逆转 AMD 病理生理学的有前途的候选物。
