Photoreceptor apoptosis is recognized as one key pathogenesis of retinal degeneration, the counteraction of which represents a promising approach to safeguard visual function. Recently, mesenchymal stem cell transplantation (MSCT) has demonstrated immense potential to treat ocular disorders, in which extracellular vesicles (EVs), particularly exosomes, have emerged as effective ophthalmological therapeutics. However, whether and how MSCT protects photoreceptors against apoptotic injuries remains largely unknown. Here, we discovered that intravitreal MSCT counteracted photoreceptor apoptosis and alleviated retinal morphological and functional degeneration in a mouse model of photoreceptor loss induced by N-methyl-N-nitrosourea (MNU). Interestingly, effects of MSCT were inhibited after blockade of exosomal generation by GW4869 preconditioning. Furthermore, MSC-derived exosomal transplantation (EXOT) effectively suppressed MNU-provoked photoreceptor injury. Notably, therapeutic efficacy of MSCT and EXOT on MNU-induced retinal degeneration was long-lasting as photoreceptor preservance and retinal maintenance were detected even after 1–2 months post to injection for only once. More importantly, using a natural occurring retinal degeneration model caused by a nonsense mutation of Phosphodiesterase 6b gene (Pde6b^mut), we confirmed that MSCT and EXOT prevented photoreceptor loss and protected long-term retinal function. In deciphering therapeutic mechanisms regarding potential exosome-mediated communications, we identified that miR-21 critically maintained photoreceptor viability against MNU injury by targeting programmed cell death 4 (Pdcd4) and was transferred from MSC-derived exosomes in vivo for functional regulation. Moreover, miR-21 deficiency aggravated MNU-driven retinal injury and was restrained by EXOT. Further experiments revealed that miR-21 mediated therapeutic effects of EXOT on MNU-induced photoreceptor apoptosis and retinal dysfunction. These findings uncovered the efficacy and mechanism of MSCT-based photoreceptor protection, indicating exosomal miR-21 as a therapeutic for retinal degeneration.

感光细胞凋亡被认为是视网膜变性的一个关键发病机制，其抵消作用代表了一种有前途的保护视觉功能的方法。最近，间充质干细胞移植 (MSCT) 已显示出治疗眼部疾病的巨大潜力，其中细胞外囊泡 (EV)，尤其是外泌体，已成为有效的眼科治疗方法。然而，MSCT 是否以及如何保护光感受器免受凋亡损伤仍然很大程度上未知。在这里，我们发现玻璃体内的 MSCT 在N-甲基-N诱导的光感受器损失小鼠模型中抵消了光感受器凋亡并减轻了视网膜形态和功能退化。-亚硝基脲（MNU）。有趣的是，在通过 GW4869 预处理阻断外泌体生成后，MSCT 的作用受到抑制。此外，MSC 衍生的外泌体移植 (EXOT) 有效抑制了 MNU 引发的光感受器损伤。值得注意的是，MSCT 和 EXOT 对 MNU 诱导的视网膜变性的治疗效果是持久的，因为即使在注射后 1-2 个月后检测到光感受器保留和视网膜维持仅一次。更重要的是，使用由磷酸二酯酶 6b基因（Pde6b ^mut)，我们证实 MSCT 和 EXOT 可防止光感受器损失并保护长期视网膜功能。在破译有关潜在外泌体介导的通讯的治疗机制时，我们发现 miR-21 通过靶向程序性细胞死亡 4 (Pdcd4) 关键维持光感受器对 MNU 损伤的活力，并在体内从 MSC 衍生的外泌体转移以进行功能调节。此外，miR-21 缺乏会加重 MNU 驱动的视网膜损伤，并受到 EXOT 的抑制。进一步的实验表明，miR-21 介导 EXOT 对 MNU 诱导的感光细胞凋亡和视网膜功能障碍的治疗作用。这些发现揭示了基于 MSCT 的光感受器保护的功效和机制，表明外泌体 miR-21 作为视网膜变性的治疗剂。