Remodeling retinal Müller glial fate, including gliosis inhibition and pro-reprogramming, represents a crucial avenue for treating degenerative retinal diseases. Stem cell transplantation exerts effects on modulating retinal Müller glial fate. However, the optimized stem cell products and the underlying therapeutic mechanisms need to be investigated. In the present study, we found that retinal progenitor cells from human embryonic stem cell-derived retinal organoids (hERO-RPCs) transferred extracellular vesicles (EVs) into Müller cells following subretinal transplantation into RCS rats. Small EVs from hERO-RPCs (hERO-RPC-sEVs) were collected and were found to delay photoreceptor degeneration and protect retinal function in RCS rats. hERO-RPC-sEVs were taken up by Müller cells both in vivo and in vitro, and inhibited gliosis while promoting early dedifferentiation of Müller cells. We further explored the miRNA profiles of hERO-RPC-sEVs, which suggested a functional signature associated with neuroprotection and development, as well as the regulation of stem cell and glial fate. Mechanistically, hERO-RPC-sEVs might regulate the fate of Müller cells by miRNA-mediated nuclear factor I transcription factors B (NFIB) downregulation. Collectively, our findings offer novel mechanistic insights into stem cell therapy and promote the development of EV-centered therapeutic strategies.

中文翻译：

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类器官来源的人视网膜干细胞的小细胞外囊泡通过 miRNA 重塑 Müller 细胞命运：视网膜变性的新疗法

重塑视网膜穆勒神经胶质细胞的命运，包括神经胶质细胞增生抑制和前重编程，是治疗退行性视网膜疾病的重要途径。干细胞移植对调节视网膜穆勒神经胶质细胞的命运产生影响。然而，优化的干细胞产品和潜在的治疗机制还需要研究。在本研究中，我们发现来自人胚胎干细胞衍生的视网膜类器官（hERO-RPC）的视网膜祖细胞在视网膜下移植到RCS大鼠体内后将细胞外囊泡（EV）转移到Müller细胞中。收集来自 hERO-RPC（hERO-RPC-sEV）的小 EV，发现其可以延缓 RCS 大鼠的光感受器变性并保护视网膜功能。 hERO-RPC-sEVs 在体内和体外均被 Müller 细胞摄取，并抑制神经胶质增生，同时促进 Müller 细胞的早期去分化。我们进一步探索了 hERO-RPC-sEV 的 miRNA 谱，这表明其具有与神经保护和发育以及干细胞和胶质细胞命运调节相关的功能特征。从机制上讲，hERO-RPC-sEVs 可能通过 miRNA 介导的核因子 I 转录因子 B (NFIB) 下调来调节 Müller 细胞的命运。总的来说，我们的研究结果为干细胞治疗提供了新的机制见解，并促进了以 EV 为中心的治疗策略的发展。