M2 microglia-derived small extracellular vesicles modulate NSC fate after ischemic stroke via miR-25-3p/miR-93-5p-TGFBR/PTEN/FOXO3 axis
Open accessAbstract
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.
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- Authors
- Zhang, Q., Yi, Y., Chen, T., Ai, Y., Chen, Z., Liu, G., Tang, Z., Chen, J., Xu, T., Chen, X., Liu, J., & Xia, Y.
- Affiliations
- Xiangya Hospital Central South University (CN)
- Rutgers, The State University of New Jersey (US)
- Research Institute of Tsinghua University in Shenzhen (CN)
- Corresponding author
- Chen, Xin
- Liu, Jinfang
- Xia, Yuguo
- Venue
- Journal of Nanobiotechnology
- Published
- 2025-04-23
- Volume
- 23
- Issue
- 1
- Pages
- 311-311
- ISSN
- 1477-3155 (ISSN-L)
- PMC
- PMC12020034
- OpenAlex
- W4409725759
- Cited by
- 27
- References
- 64
- Citations by year
- 2026: 25 · 2025: 2
- FWCI
- 6.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Nanobiotechnology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Natural Science Foundation of Hunan Province (2024JJ6657, 2024JJ5623)
- National Natural Science Foundation of China (82371407, 82201543)
- National Postdoctoral Program for Innovative Talents (BX20220356)
- China Postdoctoral Science Foundation (2022M723562)
- Young Foundation of Xiangya hospital (2021Q01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- M2 microglia, small extracellular vesicles, ischemic stroke, neural stem cells, neurogenesis, miR-25-3p, miR-93-5p, PTEN, FOXO3, neuronal differentiation, subventricular zone, oxygen-glucose deprivation, middle cerebral artery occlusion, sensorimotor recovery, IL-4
- MeSH terms
- Extracellular Vesicles, Forkhead Box Protein O3, Ischemic Stroke, Animals, Cell Differentiation, Male, Mice, Inbred C57BL, Microglia, Infarction, Middle Cerebral Artery, MicroRNAs, Cell Proliferation, PTEN Phosphohydrolase, Mice, Neurogenesis, Neural Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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