中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (10): 2238-2246.doi: 10.4103/1673-5374.336871

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

缺氧缺血性脑损伤细胞外囊泡输送的miR-21a-5p介导小胶质细胞分化

  

  • 出版日期:2022-10-15 发布日期:2022-03-16
  • 基金资助:
    国家自然科学基金81873768、82072535、81671213、81770436和中国国家慢性非传染性疾病重点项目2016YFC1300403

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

Dan-Qing Xin1, Yi-Jing Zhao1, Ting-Ting Li1, Hong-Fei Ke1, Cheng-Cheng Gai1, Xiao-Fan Guo2, Wen-Qiang Chen3, De-Xiang Liu4, Zhen Wang1#br#   

  1. 1Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China; 2Department of Neurology, Loma Linda University Health, Loma Linda, CA, USA; 3Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China; 4Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
  • Online:2022-10-15 Published:2022-03-16
  • Contact: De-Xiang Liu, PhD, liudexiang@sdu.edu.cn; Zhen Wang, PhD, wangzhen@sdu.edu.cn.
  • Supported by:
    The work was supported by the National Natural Science Foundation of China, Nos. 81873768, 82072535, 81671213 (to ZW), 81770436 (to WQC) and the National Key Project of Chronic Non-Communicable Disease of China, No. 2016YFC1300403 (to WQC).

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摘要：

作者既往报道，间充质干细胞源性细胞外囊泡（EVs）在缺氧缺血性脑损伤中表现出保护作用，该作用与细胞外囊泡的抗炎作用有关；然而，这种作用所涉及的机制尚待进一步研究。实验通过体外氧糖剥夺实验模拟缺氧缺血性脑损伤后发现，间充质干细胞源性细胞外囊泡干预提高了BV-2细胞暴露于氧糖剥夺后的细胞活力。间充质干细胞源性细胞外囊泡处理阻碍了小胶质细胞介导的神经炎症，使小胶质细胞转向M2极化，并抑制了体外和新生小鼠缺氧缺血性脑损伤后小胶质细胞中选择性信号转导和转录激活剂3（STAT3）的磷酸化。鉴于miR-21a-5p是间充质干细胞源性细胞外囊泡中与STAT3途径相互作用的最高度表达的miRNA，实验进一步对途径进行了研究。值得注意的是，间充质干细胞源性细胞外囊泡处理增加了BV-2细胞中缺氧缺血性脑损伤降低的miR-21a-5p水平。间充质干细胞源性细胞外囊泡中的miR-21a-5p水平的降低部分减弱了其在体外和体内缺氧缺血性脑损伤暴露后对小胶质细胞极化和STAT3磷酸化的影响。该研究表明，间充质干细胞源性细胞外囊泡通过miR-21a-5p途径靶向STAT3，从而诱导小胶质细胞M2极化，减轻新生小鼠的缺氧缺血性脑损伤。

https://orcid.org/0000-0001-5023-4874 (De-Xiang Liu); https://orcid.org/0000-0003-3173-6961 (Zhen Wang)

Abstract: 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.

Key words: extracellular vesicles, hypoxia-ischemia, mesenchymal stromal cells, microglia, miR-21a-5p, neuroinflammation, oxygen-glucose deprivation, STAT3