Liu Cong, Xiang Jinjin, Chen Yueqin, He Chang, Tong Jun, Liao Yinglin, Lei Huangyi, Sun Lingyun, Yao Genhong, Xie Zhenggao
Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
Department of Ophthalmology, Jiangdu People's Hospital Affiliated to Medical College of Yangzhou University, Yangzhou, 225200, China.
Cell Death Discov. 2025 May 8;11(1):226. doi: 10.1038/s41420-025-02439-3.
Diabetic retinopathy (DR) ranks among the primary causes of adult blindness globally. Oxidative stress and mitochondrial dysfunction play a critical role in the progression of DR. Mounting data indicated that small extracellular vesicles (sEVs) of mesenchymal stem cell (MSC) have the ability to transport bioactive chemicals to target cells, leading to changes in their phenotype. Nevertheless, it remains elusive how MSC-derived sEVs regulate oxidative stress and mitochondrial function in DR. MSC-sEVs was intravitreally injected to streptozotocin (STZ)-treated Sprague-Dawley rats to assess the therapeutic effects on DR. The underlying regulatory mechanism was investigated by coculturing advanced glycation end-products (AGEs)-induced rat Müller cells with/without PTP1B overexpression with MSC-sEVs in vitro, with or without miR-125a-5p suppression. Intravitreal injection of MSC-sEVs improved histological morphology and blood-retinal barrier function, alleviated Müller gliosis, decreased PTP1B expression, redox stress and apoptosis in retina of diabetic rat. MSC-sEVs decreased the accumulation of ROS and improved the structure and function of mitochondria of Müller cells with AGEs treatment. Mechanically, MSC-sEVs activated the mitophagy of AGEs-treated Müller cells, represented by an increased expression of the LC3II/LC3I ratio, TOM20, PINK1 and Parkin along with a decreased expression of P62. Importantly, miR-125a-5p inhibitor abolished the protective effects of MSC-sEVs. Furthermore, the overexpression of PTP1B in Müller cells reduced the effects of MSC-sEVs. These findings suggested that miR-125a-5p of MSC-sEVs alleviates Müller cells injury in DR by modulating PINK1/Parkin-mediated mitophagy via PTP1B pathway.
糖尿病视网膜病变（DR）是全球成人失明的主要原因之一。氧化应激和线粒体功能障碍在DR的进展中起关键作用。越来越多的数据表明，间充质干细胞（MSC）的小细胞外囊泡（sEVs）能够将生物活性化学物质转运到靶细胞，导致其表型发生变化。然而，MSC衍生的sEVs如何调节DR中的氧化应激和线粒体功能仍不清楚。将MSC-sEVs玻璃体内注射到链脲佐菌素（STZ）处理的Sprague-Dawley大鼠中，以评估其对DR的治疗效果。通过在体外将晚期糖基化终产物（AGEs）诱导的大鼠Müller细胞与过表达/未过表达PTP1B的细胞与MSC-sEVs共培养，并抑制或不抑制miR-125a-5p，研究其潜在的调节机制。玻璃体内注射MSC-sEVs可改善组织形态和血视网膜屏障功能，减轻Müller细胞增生，降低糖尿病大鼠视网膜中PTP1B表达、氧化还原应激和细胞凋亡。MSC-sEVs减少了ROS的积累，并改善了经AGEs处理的Müller细胞的线粒体结构和功能。机制上，MSC-sEVs激活了经AGEs处理的Müller细胞的线粒体自噬，表现为LC3II/LC3I比值、TOM20、PINK1和Parkin表达增加，而P62表达降低。重要的是，miR-125a-5p抑制剂消除了MSC-sEVs的保护作用。此外，Müller细胞中PTP1B的过表达降低了MSC-sEVs的作用。这些发现表明 MSC-sEVs中的miR-125a-5p通过PTP1B途径调节PINK1/Parkin介导的线粒体自噬，从而减轻DR中Müller细胞的损伤。
