M2 microglia-derived small extracellular vesicles modulate NSC fate after ischemic stroke via miR-25-3p/miR-93-5p-TGFBR/PTEN/FOXO3 axis

作者：Qian Zhang, Yan Yi, Tiange Chen, Yuejie Ai, Ziyang Chen, Ganzhi Liu, Zexuan Tang, Jianwei Chen, Tao Xu, Xin Chen, Jinfang Liu, Yuguo Xia · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03390-2 · 被引用次数：21 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Neurogenesis and neuroplasticity mechanisms、Extracellular vesicles in disease

BACKGROUND: Endogenous neurogenesis could promote stroke recovery. Furthermore, anti-inflammatory phenotypical microglia (M2-microglia) could facilitate Neural Stem Cell (NSC)-mediated neurogenesis following Ischemic Stroke (IS). Nonetheless, the mechanisms through which M2 microglia influence NSC-mediated neurogenesis post-IS remain unclear. On the other hand, M2 microglia-derived small Extracellular Vesicles (M2-sEVs) could exert phenomenal biological effects and play significant roles in cell-to-cell interactions, highlighting their potential involvement in NSC-mediated neurogenesis post-IS, forming the basis of this study. METHODS: M2-sEVs were first isolated from IL-4-stimulated microglia. For in vivo tests, M2-sEVs were intravenously injected into mice every day for 14 days after transient Middle Cerebral Artery Occlusion (tMCAO). Following that, the infarct volume and neurological function, as well as NSC proliferation in the Subventricular Zone and dentate gyrus, migration, and differentiation in the infarct area, were examined. For in vitro tests, M2-sEVs were administered to NSC subjected to Oxygen-Glucose Deprivation (OGD) and then reoxygenation, after which NSC proliferation and differentiation were assessed. Finally, M2-sEVs were subjected to microRNA sequencing to explore the regulatory mechanisms. RESULTS: Our findings revealed that M2-sEVs reduced the infarct volume and increased the neurological score in mice post-tMCAO. Furthermore, M2-sEV treatment promoted...