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 (12): 2717-2724.doi: 10.4103/1673-5374.339489

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

骨髓间充质干细胞来源外泌体可抑制创伤性脑损伤后的神经炎症

  

  • 出版日期:2022-12-15 发布日期:2022-05-05
  • 基金资助:
    国家自然科学基金项目（81971159，81771317）

Exosomes derived from bone marrow mesenchymal stem cells inhibit neuroinflammation after traumatic brain injury

Liang Wen1, #, Ya-Dong Wang1, *, #, Dong-Feng Shen2, Pei-Dong Zheng1, Meng-Di Tu1, Wen-Dong You1, Yuan-Run Zhu1, Hao Wang1, Jun-Feng Feng3, Xiao-Feng Yang1, *   

  1. 1The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; 2Department of Intensive Care Unit, The First Hospital of Jiaxing, Jiaxing, Zhejiang Province, China; 3Department of Neurosurgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  • Online:2022-12-15 Published:2022-05-05
  • Contact: Xiao-Feng Yang, MD, zjcswk@zju.edu.cn; Ya-Dong Wang, MD, 11718340@zju.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81971159 (to LW), 81771317 (to JFF).

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摘要：

有研究认为来源于骨髓间充质干细胞的外泌体可通过调节小胶质细胞表型来抑制神经炎症并促进神经修复。然而，这一过程所涉及的分子机制尚未阐明。为了解骨髓间充质干细胞来源的外泌体对神经炎症的潜在作用机制，实验首先通过体外共培养实验证实了骨髓间充质干细胞及其外泌体均能促进活化的BV2小胶质细胞向抗炎表型的极化，抑制促炎细胞因子的表达，并促进抗炎细胞因子的表达。进一步体内实验发现尾静脉注射外泌体可减少创伤性脑损伤小鼠模型皮质组织中细胞的凋亡，抑制神经炎症，并促进小胶质细胞向抗炎表型的转化。然后通过微小RNA测序筛选出部分与神经炎症相关的微小RNA并进行验证，发现microRNA-181b 似乎积极参与了这一过程。最后以慢病毒调控创伤性脑损伤小鼠脑组织中miR181b的表达，发现miR181b过表达可有效降低脑外伤后细胞凋亡和神经炎症反应，并促进小胶质细胞向抗炎表型的转化，且白细胞介素10/STAT3通路在此过程被激活。上述结果表明间充质干细胞外泌体抑制创伤性脑损伤后的神经炎症作用可能是通过其含有的miR181b作用于白细胞介素10/STAT3通路来实现的。

https://orcid.org/0000-0003-0994-5118 (Xiao-Feng Yang); https://orcid.org/0000-0002-0981-7717 (Ya-Dong Wang)

关键词: 骨髓间充质干细胞, 外泌体, BV2小胶质细胞, 细胞表型, 神经炎症, 创伤性脑损伤, 细胞凋亡, 慢病毒转染, microRNA-181b, 白细胞介素10, STAT3

Abstract: Exosomes derived from bone marrow mesenchymal stem cells can inhibit neuroinflammation through regulating microglial phenotypes and promoting nerve injury repair. However, the underlying molecular mechanism remains unclear. In this study, we investigated the mechanism by which exosomes derived from bone marrow mesenchymal stem cells inhibit neuroinflammation. Our in vitro co-culture experiments showed that bone marrow mesenchymal stem cells and their exosomes promoted the polarization of activated BV2 microglia to their anti-inflammatory phenotype, inhibited the expression of proinflammatory cytokines, and increased the expression of anti-inflammatory cytokines. Our in vivo experiments showed that tail vein injection of exosomes reduced cell apoptosis in cortical tissue of mouse models of traumatic brain injury, inhibited neuroinflammation, and promoted the transformation of microglia to the anti-inflammatory phenotype. We screened some microRNAs related to neuroinflammation using microRNA sequencing and found that microRNA-181b seemed to be actively involved in the process. Finally, we regulated the expression of miR181b in the brain tissue of mouse models of traumatic brain injury using lentiviral transfection. We found that miR181b overexpression effectively reduced apoptosis and neuroinflamatory response after traumatic brain injury and promoted the transformation of microglia to the anti-inflammatory phenotype. The interleukin 10/STAT3 pathway was activated during this process. These findings suggest that the inhibitory effects of exosomes derived from bone marrow mesenchymal stem cells on neuroinflamation after traumatic brain injury may be realized by the action of miR181b on the interleukin 10/STAT3 pathway. 

Key words: apoptosis, bone marrow mesenchymal stem cells, BV2 microglia, exosome, interleukin 10, lentiviral transfection, microRNA-181b, neuroinflammation, phenotype, signal transducer and activator of transcription 3, traumatic brain injury