Tong Jun, Chen Yueqin, Zhang Ye, Liu Cong, He Chang, Liu Yajun, Liao Yinglin, Chen Fang, Yao Genhong, Xie Zhenggao
Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Department of Ophthalmology, Northern Jiangsu People's Hospital, Yangzhou University, Yangzhou, China.
Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Exp Eye Res. 2025 Nov;260:110586. doi: 10.1016/j.exer.2025.110586. Epub 2025 Aug 19.
Diabetic retinopathy (DR), considered as a neurovascular disorder, significantly causes permanent vision loss and blindness worldwide among working-age adults. The inflammation caused by M1-like microglia is involved in DR. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) is an attractive candidate for inflammation modulation. However, the regulatory effect of sEVs secreted by MSCs on M1 differentiation of microglia in diabetic retinopathy has not been thoroughly investigated. In this study, intravitreal injection of sEVs reduced retinal inflammation, mitigated vascular leakage, and suppressed M1-like microglia via the HMGB1/TLR4 signaling pathway. Based on MSC-sEVs miRNA sequencing, bioinformatics prediction, and dual-luciferase reporter assay, miR-29a-3p was identified as a key effector in the modulation of M1-like microglia through the down-regulation of HMGB1. The silencing of miR-29a-3p in MSC-sEVs negated their therapeutic efficacy in STZ-induced diabetic rats and human microglial cells (HMC3) treated with advanced glycation end products (AGEs). Silencing miR-29a-3p in MSC-sEVs reversed the therapeutic effects of MSC-sEVs on STZ-induced rats and advanced glycation end products (AGEs)-treated HMC3. Additionally, overexpression of miR-29a-3p could suppress M1-like microglia, which could be effectively reversed by overexpressing HMGB1. Overall, this study demonstrated that MSC-sEVs carrying miR-29a-3p attenuate retinal injury in diabetic rats by reducing M1 microglia polarization through the targeting of HMGB1, thereby reducing inflammation and protecting the blood-retinal barrier (BRB). MSC-sEVs and miRNAs may be explored as promising therapeutic targets for DR.
糖尿病视网膜病变（DR）被认为是一种神经血管疾病，在全球范围内，它是导致工作年龄成年人永久性视力丧失和失明的重要原因。M1样小胶质细胞引起的炎症与DR有关。间充质干细胞（MSC）衍生的小细胞外囊泡（sEVs）是调节炎症的一个有吸引力的候选者。然而，MSC分泌的sEVs对糖尿病视网膜病变中小胶质细胞M1分化的调节作用尚未得到充分研究。在本研究中，玻璃体内注射sEVs可减轻视网膜炎症、缓解血管渗漏，并通过HMGB1/TLR4信号通路抑制M1样小胶质细胞。基于MSC-sEVs的miRNA测序、生物信息学预测和双荧光素酶报告基因检测，miR-29a-3p被确定为通过下调HMGB1来调节M1样小胶质细胞的关键效应分子。在MSC-sEVs中沉默miR-29a-3p会消除其对链脲佐菌素诱导的糖尿病大鼠和用晚期糖基化终产物（AGEs）处理的人小胶质细胞（HMC3）的治疗效果。在MSC-sEVs中沉默miR-29a-3p会逆转MSC-sEVs对链脲佐菌素诱导的大鼠和晚期糖基化终产物（AGEs）处理的HMC3的治疗作用。此外，miR-29a-3p的过表达可抑制M1样小胶质细胞，而过表达HMGB1可有效逆转这种抑制作用。总体而言，本研究表明，携带miR-29a-3p的MSC-sEVs通过靶向HMGB1减少M1小胶质细胞极化，从而减轻糖尿病大鼠的视网膜损伤，进而减轻炎症并保护血视网膜屏障（BRB）。MSC-sEVs和miRNAs有望成为DR的治疗靶点。
