The delivery of miR-21a-5p by extracellular vesicles induces microglial polarization via the STAT3 pathway following hypoxia-ischemia in neonatal mice

• Published in: Neural regeneration research 2022-10, Vol.17 (10), p.2238-2246
• Main Authors: Xin, Dan-Qing, Zhao, Yi-Jing, Li, Ting-Ting, Ke, Hong-Fei, Gai, Cheng-Cheng, Guo, Xiao-Fan, Chen, Wen-Qiang, Liu, De-Xiang, Wang, Zhen
• Format: Article
• Language: English
• Subjects: Extracellular vesicles; extracellular vesicles; hypoxia-ischemia; mesenchymal stromal cells; microglia; mir-21a-5p; neuroinflammation; oxygen-glucose deprivation; stat3; Hypoxia; Ischemia; Phosphorylation; Traumatic brain injury
• ISSN: 1673-5374; 1876-7958
• DOI: 10.4103/1673-5374.336871

Extracellular vesicles (EVs) from mesenchymal stromal cells (MSCs) have previously been shown to protect against brain injury caused by hypoxia-ischemia (HI). The neuroprotective effects have been found to relate to the anti-inflammatory effects of EVs. However, the underlying mechanisms have not previously been determined. In this study, we induced oxygen-glucose deprivation in BV-2 cells (a microglia cell line), which mimics HI in vitro, and found that treatment with MSCs-EVs increased the cell viability. The treatment was also found to reduce the expression of pro-inflammatory cytokines, induce the polarization of microglia towards the M2 phenotype, and suppress the phosphorylation of selective signal transducer and activator of transcription 3 (STAT3) in the microglia. These results were also obtained in vivo using neonatal mice with induced HI. We investigated the potential role of miR-21a-5p in mediating these effects, as it is the most highly expressed miRNA in MSCs-EVs and interacts with the STAT3 pathway. We found that treatment with MSCs-EVs increased the levels of miR-21a-5p in BV-2 cells, which had been lowered following oxygen-glucose deprivation. When the level of miR-21a-5p in the MSCs-EVs was reduced, the effects on microglial polarization and STAT3 phosphorylation were reduced, for both the in vitro and in vivo HI models. These results indicate that MSCs-EVs attenuate HI brain injury in neonatal mice by shuttling miR-21a-5p, which induces microglial M2 polarization by targeting STAT3.