Photoreceptor protection by mesenchymal stem cell transplantation identifies exosomal MiR-21 as a therapeutic for retinal degeneration.
Photoreceptor protection by mesenchymal stem cell transplantation identifies exosomal MiR-21 as a therapeutic for retinal degeneration.
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间充质干细胞移植对光感受器的保护表明外泌体 MiR-21 可用于治疗视网膜变性
DOI：
10.1038/s41418-020-00636-4
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发表时间：
2021-03
影响因子：
12.4
通讯作者：
Hu CH
中科院分区：
文献类型：
--
作者：
Deng CL;Hu CB;Ling ST;Zhao N;Bao LH;Zhou F;Xiong YC;Chen T;Sui BD;Yu XR;Hu CH
光感受器凋亡是视网膜变性的重要发病机制之一，对抗光感受器凋亡是保护视功能的重要途径。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），特别是外泌体，已成为有效的眼科治疗剂。然而，MSCT是否以及如何保护光感受器免受凋亡损伤仍然是未知的。在这里，我们发现，在由N-甲基-N-亚硝基脲（MNU）诱导的感光细胞丧失的小鼠模型中，玻璃体内MSCT抵消感光细胞凋亡，减轻视网膜形态和功能退化。有趣的是，GW 4869预处理阻断外泌体的产生后，MSCT的作用受到抑制。此外，MSC衍生的外泌体移植（EXOT）有效地抑制了MNU引起的感光细胞损伤。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个月仅一次也能检测到感光细胞排斥和视网膜维持。更重要的是，使用由磷酸二酯酶6 b基因（Pde 6 bmut）无义突变引起的自然发生的视网膜变性模型，我们证实了MSCT和EXOT可以防止感光细胞丧失并保护长期的视网膜功能。在解释关于潜在的外来体介导的通信的治疗机制时，我们确定了miR-21通过靶向程序性细胞死亡4（Pdcd 4）来关键地维持感光细胞活力对抗MNU损伤，并且在体内从MSC衍生的外来体转移用于功能调节。此外，miR-21缺陷加重了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介导了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的感光细胞保护的功效和机制，表明外泌体miR-21可作为视网膜变性的治疗剂。
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 byN-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 ofPhosphodiesterase 6bgene (Pde6bmut), 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.
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