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

小胶质细胞 白质 基因敲除 再髓鞘化 缺血 髓鞘 体内 药理学 医学 细胞生物学 生物 神经科学 免疫学 细胞凋亡 炎症 中枢神经系统 内科学 生物化学 生物技术 磁共振成像 放射科
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 Latif Khan,Qing Xie,Yongting Wang,Yaohui Tang,Zhijun Zhang,Guo‐Yuan Yang
出处
期刊:Theranostics [Ivyspring International Publisher]
卷期号:12 (7): 3553-3573 被引量:65
标识
DOI:10.7150/thno.68895
摘要

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 miR-23a-5p in M2-EVs reversed the beneficial effects of M2-EVs both in vitro and in vivo.Luciferase reporter assay showed that miR-23a-5p directly targeted Olig3.Conclusion: Our results demonstrated that M2 microglia could communicate to OPCs through M2-EVs and promote white matter repair via miR-23a-5p possibly by directly targeting Olig3 after ischemic stroke, suggesting M2-EVs is a novel and promising therapeutic strategy for white matter repair in stroke and demyelinating disease.
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