Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, 710032, Shaanxi, China.
Cell Death Differ. 2021 Mar;28(3):1041-1061. doi: 10.1038/s41418-020-00636-4. Epub 2020 Oct 20.
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), 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.
光感受器凋亡被认为是视网膜变性的一个关键发病机制，其拮抗作用代表了一种保护视觉功能的有前途的方法。最近，间充质干细胞移植 (MSCT) 已被证明在治疗眼部疾病方面具有巨大的潜力，其中细胞外囊泡 (EVs)，特别是外泌体，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细胞凋亡损伤在很大程度上尚不清楚。在这里，我们发现玻璃体内 MSCT 可拮抗光感受器凋亡，并减轻由 N-甲基-N-亚硝基脲 (MNU) 诱导的光感受器丧失的小鼠模型中的视网膜形态和功能变性。有趣的是，用 GW4869 预处理阻断外泌体生成后，MSCT 的作用受到抑制。此外，MSC 衍生的外体移植 (EXOT) 可有效抑制 MNU 引起的光感受器损伤。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，因为即使在注射后仅 1-2 个月，也能检测到光感受器的保存和视网膜的维持。更重要的是，使用由磷酸二酯酶 6b 基因 (Pde6b) 的无意义突变引起的自然发生的视网膜变性模型，我们证实 MSCT 和 EXOT 可防止光感受器丧失并保护长期视网膜功能。在阐明潜在的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) 对光感受器在 MNU 损伤中的存活至关重要，并在体内从 MSC 衍生的外体中转移以进行功能调节。此外，miR-21 缺乏加剧了 MNU 驱动的视网膜损伤，并被 EXOT 抑制。进一步的实验表明，miR-21 介导了 EXOT 对 MNU 诱导的光感受器凋亡和视网膜功能障碍的治疗作用。这些发现揭示了 MSCT 基于光感受器保护的疗效和机制，表明外泌体 miR-21 是治疗视网膜变性的一种方法。
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