Qian Hai-Dong, Song Xiang-Yuan, He Guan-Wen, Peng Xue-Ni, Chen Ying, Huang Pan, Zhang Jing, Lin Xiao-Yan, Gao Qiao, Zhu Sen-Miao, Li Tong, Chi Zai-Long
State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
National Clinical Research Center for Ocular Diseases, Eye Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
Adv Healthc Mater. 2025 May;14(12):e2404306. doi: 10.1002/adhm.202404306. Epub 2025 Mar 25.
Retinal ganglion cell (RGC) degeneration leads to irreversible blindness. Müller glia (MG) play pivotal roles in retinal homeostasis and disease through paracrine signaling. Small extracellular vesicles (sEVs) are bioactive nanomaterials derived from all types of live cells and are recognized as a potential strategy for neuroprotective therapy. The aim of this study is to investigate the potential roles of MG-derived sEVs (MG-sEVs) in a mouse model of optic nerve injury (ONC). It is found that MG-sEVs treatment effectively mitigates RGC degeneration and suppresses microglial activation, thereby improves visual function in ONC mice. Retinal transcriptomic analysis reveals a strong correlation between C-x3-c motif chemokine ligand 1 (Cx3cl1)-mediated glial activation and inflammation. Subsequently, it is confirmed that the expression levels of Cx3cl1 and proinflammatory cytokines are significantly decreased in retinas treated with MG-sEVs. The components analysis of MG-sEVs cargo identifies that miR-125b-5p and miR-16-5p target Cx3cl1 gene to regulate its expression. It is also observed that Cx3cl1 colocalizes on the microglia of transgenic C-x3-c motif chemokine receptor 1 (Cx3Cr1)-GFP mice. In conclusion, MG-sEVs mitigate RGC degeneration by suppressing microglial activation via Cx3cl1-Cx3cr1 signaling. This research provides additional opportunities for the treatment of RGC degeneration.
视网膜神经节细胞（RGC）变性会导致不可逆的失明。穆勒胶质细胞（MG）通过旁分泌信号在视网膜内环境稳态和疾病中发挥关键作用。小细胞外囊泡（sEVs）是源自所有类型活细胞的生物活性纳米材料，被认为是神经保护治疗的一种潜在策略。本研究的目的是探讨MG衍生的sEVs（MG-sEVs）在视神经损伤（ONC）小鼠模型中的潜在作用。研究发现，MG-sEVs治疗可有效减轻RGC变性并抑制小胶质细胞活化，从而改善ONC小鼠的视觉功能。视网膜转录组分析揭示了C-X3-C基序趋化因子配体1（Cx3cl1）介导的神经胶质细胞活化与炎症之间存在密切相关性。随后，证实MG-sEVs处理的视网膜中Cx3cl1和促炎细胞因子的表达水平显著降低。对MG-sEVs货物的成分分析确定miR-125b-5p和miR-16-5p靶向Cx3cl1基因以调节其表达。还观察到Cx3cl1在转基因C-X3-C基序趋化因子受体1（Cx3Cr1）-绿色荧光蛋白（GFP）小鼠的小胶质细胞上共定位。总之，MG-sEVs通过Cx3cl1-Cx3cr1信号通路抑制小胶质细胞活化，从而减轻RGC变性。这项研究为RGC变性的治疗提供了更多机会。
