M2 Microglia Extracellular Vesicle miR-124 Regulates Neural Stem Cell Differentiation in Ischemic Stroke via AAK1/NOTCH

作者：Yaying Song, Rubing Shi, Yingjun Liu, Fengzhen Cui, Lu Han, Chuandong Wang, Tingting Chen, Zongwei Li, Zhijun Zhang, Yaohui Tang, Guo‐Yuan Yang, Yangtai Guan · 发表于：Stroke · 年份：2023 · DOI：10.1161/strokeaha.122.041611 · 被引用次数：65 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Extracellular vesicles in disease、Neurogenesis and neuroplasticity mechanisms

BACKGROUND: Small extracellular vesicles (sEVs) derived from M2 microglia (M2-microglia-derived small extracellular vesicles [M2-sEVs]) contribute to central nervous system repair, although the underlying mechanism remains unknown. In this study, we aimed to identify the mechanism through which microRNA-124 (miR-124) carried in sEVs promotes neural stem cell (NSC) proliferation and neuronal differentiation in the ischemic mouse brain. METHODS: M2-sEVs with or without miR-124 knockdown were injected intravenously for 7 consecutive days after transient middle cerebral artery occlusion surgery. The atrophy volume, neurological score, and degree of neurogenesis were examined at different time points after ischemic attack. NSCs treated with different sEVs were subjected to proteomic analysis. Target protein concentrations were quantified, and subsequent bioinformatic analysis was conducted to explore the key signaling pathways. RESULTS: M2-sEV transplantation promoted functional neurological recovery following transient middle cerebral artery occlusion injury. M2-sEV treatment decreased the brain atrophy volume, neurological score, and mortality rate. The effect was reserved by knockdown of miR-124 in M2-sEVs. M2-sEVs promoted proliferation and differentiation of mature neuronal NSCs in vivo. Proteomic analysis of NSC samples treated with M2-sEVs with and without miR-124 knockdown revealed that AAK1 (adaptor-associated protein kinase 1) was the key responding protein in NSCs. The ...