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M2 microglia-derived small extracellular vesicles modulate NSC fate after ischemic stroke via
Qian Zhang1,2, Yan Yi3,2, Tiange Chen1,2
1Department of Neurosurgery, Xiangya Hospital Central South University, Changsha, Hunan, CN, 410008, China.
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 NSC proliferation and neuronal differentiation both in vivo and in vitro. Additionally, microRNA sequencing revealed miR-93-5p and miR-25-3p enrichment in M2-sEVs. Inhibitors of these miRNAs prevented TGFBR, PTEN, and FOXO3 downregulation in NSC, reversing M2-sEVs' beneficial effects on neurogenesis and sensorimotor recovery.
Conclusions:
M2-sEVs increased NSC proliferation and neuronal differentiation, and protected against IS, at least partially, via delivering miR-25-3p and miR-93-5p to downregulate TGFBR, PTEN, and FOXO3 expression in NSC.
Insights
M2 microglia-derived small extracellular vesicles (M2-sEVs) promote neural stem cell neurogenesis and stroke recovery. They deliver specific microRNAs to downregulate key genes, enhancing therapeutic potential for ischemic stroke.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Cell Biology
Background:
- Endogenous neurogenesis aids stroke recovery.
- Anti-inflammatory M2 microglia can enhance neural stem cell (NSC)-mediated neurogenesis after ischemic stroke (IS).
- Mechanisms of M2 microglia influencing NSC neurogenesis post-IS are unclear, but M2 microglia-derived small extracellular vesicles (M2-sEVs) show potential.
Purpose of the Study:
- To investigate the role of M2-sEVs in NSC-mediated neurogenesis and functional recovery post-IS.
- To elucidate the underlying molecular mechanisms involving microRNAs within M2-sEVs.
Main Methods:
- Isolated M2-sEVs from IL-4-stimulated microglia.
- Administered M2-sEVs intravenously to mice post-transient Middle Cerebral Artery Occlusion (tMCAO).
- Assessed infarct volume, neurological function, NSC proliferation/migration/differentiation in vivo and in vitro, and performed microRNA sequencing on M2-sEVs.
Main Results:
- M2-sEVs reduced infarct volume and improved neurological scores in mice post-tMCAO.
- M2-sEV treatment promoted NSC proliferation and neuronal differentiation both in vivo and in vitro.
- M2-sEVs were enriched with miR-93-5p and miR-25-3p, which downregulated TGFBR, PTEN, and FOXO3 in NSCs, reversing beneficial effects when inhibited.
Conclusions:
- M2-sEVs enhance NSC proliferation and neuronal differentiation, offering protection against ischemic stroke.
- The therapeutic effects are partly mediated by miR-25-3p and miR-93-5p delivery, which downregulate TGFBR, PTEN, and FOXO3 expression in NSCs.
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