M2 microglia-derived extracellular vesicles promote white matter repair and functional recovery via miR-23a-5p after cerebral ischemia in mice

作者：Yongfang Li, Ze Liu, Yaying Song, Jiaji Pan, Yixu Jiang, Xiaojing Shi, Chang Liu, Yuanyuan Ma, Longlong Luo, Muyassar Mamtilahun, Zhiyu Shi, Haroon Khan, Qing Xie, Yongting Wang, Yaohui Tang, Zhijun Zhang, Guo‐Yuan Yang · 发表于：Theranostics · 年份：2022 · DOI：10.7150/thno.68895 · 被引用次数：149 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Extracellular vesicles in disease、MicroRNA in disease regulation

Rationale: White matter repair is critical for the cognitive and neurological functional recovery after ischemic stroke. M2 microglia are well-documented to enhance remyelination and their extracellular vesicles (EVs) mediate cellular function after brain injury. However, whether M2 microglia-derived EVs could promote white matter repair after cerebral ischemia and its underlying mechanism are largely unknown. Methods: EVs were isolated from IL-4 treated microglia (M2-EVs) and untreated microglia (M0-EVs). Adult ICR mice subjected to 90-minute transient middle cerebral artery occlusion received intravenous EVs treatment for seven consecutive days. Brain atrophy volume, neurobehavioral tests were examined within 28 days following ischemia. Immunohistochemistry, myelin transmission electron microscope and compound action potential measurement were performed to assess white matter structural remodeling, functional repair and oligodendrogenesis. The effects of M2-EVs on oligodendrocyte precursor cells (OPCs) were also examined in vitro. EVs' miRNA sequencing, specific miR-23a-5p knockdown in M2-EVs and luciferase reporter assay were used to explore the underlying mechanism. Results: M2-EVs reduced brain atrophy volume, promoted functional recovery, oligodendrogenesis and white matter repair in vivo, increased OPC proliferation, survival and differentiation in vitro. miR-23a-5p was enriched in M2-EVs and could promote OPC proliferation, survival and maturation, while knocking down...