Tong Jun, Chen Yueqin, Ling Xinru, Huang Zhenping, Yao Genhong, Xie Zhenggao
Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province 210008, People's Republic of China.
Department of Ophthalmology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province 210002, People's Republic of China.
Stem Cells. 2025 May 27;43(6). doi: 10.1093/stmcls/sxaf023.
Progressive endothelial cell injury of retinal vascular is a vital factor in diabetic retinopathy (DR) pathogenesis. Mesenchymal stem cells-derived small extracellular vesicles (MSC-sEVs) showed beneficial effects on DR. However, the effects of MSC-sEVs on endothelial dysfunction of DR and the mechanism is still unclear. In this study, MSC-sEVs mitigated retinal blood-retina barrier (BRB) impairment in rats with streptozotocin (STZ)-induced DR by reducing ferroptosis in vivo and in vitro. MSC-sEVs miRNA sequencing analysis revealed that miR-125b-5p may mediate human retina microvascular endothelial cells (HRMECs) ferroptosis and P53 as a downstream target based on dual-luciferase reporter assays. Silencing miR-125b-5p in MSC-sEVs reversed the therapeutic effects of MSC-sEVs on rats with DR and advanced glycation end products (AGEs)-treated HRMECs. Additionally, overexpression of miR-125b-5p could diminish ferroptosis in HRMECs, and this effect could be effectively reversed by overexpressing P53. This study indicated the potential therapeutic effect of MSC-sEVs on vascular endothelial function maintenance and that the delivery of sEVs carrying miR-125b-5p could prevent endothelial cell ferroptosis by inhibiting P53, thereby protecting the BRB.
视网膜血管内皮细胞的进行性损伤是糖尿病视网膜病变（DR）发病机制中的一个关键因素。间充质干细胞衍生的小细胞外囊泡（MSC-sEVs）对DR显示出有益作用。然而，MSC-sEVs对DR内皮功能障碍的影响及其机制仍不清楚。在本研究中，MSC-sEVs通过减少体内和体外的铁死亡，减轻了链脲佐菌素（STZ）诱导的DR大鼠的视网膜血视网膜屏障（BRB）损伤。MSC-sEVs的miRNA测序分析显示，基于双荧光素酶报告基因检测，miR-125b-5p可能介导人视网膜微血管内皮细胞（HRMECs）的铁死亡，且P53作为下游靶点。在MSC-sEVs中沉默miR-125b-5p可逆转MSC-sEVs对DR大鼠和晚期糖基化终产物（AGEs）处理的HRMECs的治疗作用。此外，miR-125b-5p的过表达可减少HRMECs中的铁死亡，而过表达P53可有效逆转这种作用。本研究表明MSC-sEVs对维持血管内皮功能具有潜在的治疗作用，并且携带miR-125b-5p的sEVs的递送可通过抑制P53来预防内皮细胞铁死亡，从而保护BRB。
