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.

Dan-Qing Xin;Yi-Jing Zhao;Ting-Ting Li;Hong-Fei Ke;Cheng-Cheng Gai;Xiao-Fan Guo;Wen-Qiang Chen;De-Xiang Liu;Zhen Wang

Department of Physiology,School of Basic Medical Sciences,Cheeloo College of Medicine,Shandong University,Jinan,Shandong Province,China;Department of Neurology, Loma Linda University Health,Loma Linda,CA,USA;Department of Cardiology,Qilu Hospital,Cheeloo College of Medicine,Shandong University,Jinan,Shandong Province,China;Department of Medical Psychology and Ethics,School of Basic Medicine Sciences,Cheeloo College of Medicine,Shandong University,Jinan,Shandong Province,China

中国神经再生研究（英文版）

[1]Dan-Qing Xin;Yi-Jing Zhao;Ting-Ting Li;Hong-Fei Ke;Cheng-Cheng Gai;Xiao-Fan Guo;Wen-Qiang Chen;De-Xiang Liu;Zhen Wang-.The delivery of miR-21a-5p by extracellular vesicles induces microglial polarization via the STAT3 pathway following hypoxia-ischemia in neonatal mice)[J].中国神经再生研究（英文版）,2022(10):2238-2246

delivery,21a,5p,by,extracellular,vesicles,induces,microglial,polarization,STAT3,pathway,following,hypoxia,ischemia,neonatal,mice,Extracellular,EVs,from,mesenchymal,stromal,cells,MSCs,have,previously,been,shown,against,brain,injury,caused,HI,neuroprotective,effects,found,relate,anti,inflammatory,However,underlying,mechanisms,determined,In,this,study,induced,oxygen,glucose,deprivation,BV,line,which,mimics,vitro,that,treatment,increased,viability,was,also,expression,cytokines,towards,M2,phenotype,suppress,phosphorylation,selective,signal,transducer,activator,transcription,These,results,obtained,vivo,using,We,investigated,potential,role,mediating,these,most,highly,expressed,miRNA,interacts,levels,had,lowered,When,reduced,both,models,indicate,attenuate,shuttling,targeting

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