中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (3): 560-567.doi: 10.4103/1673-5374.346551

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

来源于骨髓间充质干细胞外泌体的miR-23b可减轻脑出血后氧化应激和细胞焦亡

  

  • 出版日期:2023-03-15 发布日期:2022-08-26
  • 基金资助:
    中国国家自然科学基金项目(81571120)

Exosomal miR-23b from bone marrow mesenchymal stem cells alleviates oxidative stress and pyroptosis after intracerebral hemorrhage

Liu-Ting Hu1, 2, Bing-Yang Wang2, Yu-Hua Fan1, *, Zhi-Yi He2, *, Wen-Xu Zheng3, *   

  1. 1Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China; 2Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China; 3Geriatric Department of Dalian Friendship Hospital, Dalian, Liaoning Province, China
  • Online:2023-03-15 Published:2022-08-26
  • Contact: Yu-Hua Fan, MD, fanyuhua@mail.sysu.edu.cn or fansusan@126.com; Zhi-Yi He, MD, hezhiyi0301@sina.com; Wen-Xu Zheng, 13942600445@126.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81571120 (to ZYH).

摘要:

作者所在团队既往研究发现,miR-23b在脑出血患者血清中显著下调,提示其可能与脑出血的病理生理学机制密切相关,但尚缺乏直接证据。此次实验以右侧基底神经节注射胶原酶VII构建脑出血大鼠模型,尾静脉注射来源于骨髓间充质干细胞外泌体的miR-23b进行干预,(1)结果见大鼠的脑水肿明显减轻,行为学功能明显改善。继而发现骨髓间充质干细胞外泌体中的miR-23b可被转运至小胶质细胞/巨噬细胞,有效减轻脑出血中的氧化应激水平,且缓解脑出血后的细胞焦亡。(2)进一步以血红素刺激HT22细胞在体外模拟脑出血,发现PTEN是miR-23b的下游靶基因,外泌体miR-23b可通过调控PTEN/Nrf2通路而发挥抗氧化作用;且miR-23b可减少内源性PTEN与NLRP3的结合,并减少NLRP3炎症小体的活化,从而降低NLRP3依赖性细胞焦亡水平。(3)结果提示来源于骨髓间充质干细胞外泌体的miR-23b可通过靶向抑制PTEN而发挥抗氧化作用,并缓解NLRP3炎症小体介导的细胞焦亡,从而促进脑出血大鼠的神经功能恢复。

https://orcid.org/0000-0003-3415-4975 (Liu-Ting Hu); 

https://orcid.org/0000-0002-1172-1490 (Yu-Hua Fan); 

https://orcid.org/0000-0002-0995-0294 (Zhi-Yi He); 

https://orcid.org/0000-0002-1518-1030 (Wen-Xu Zheng)

关键词: 脑出血, 外泌体, 微小RNA, 骨髓间充质干细胞, 氧化应激, 细胞焦亡, NLRP3炎性小体, 神经炎症, miR-23b, PTEN, Nrf2

Abstract: Our previous studies showed that miR-23b was downregulated in patients with intracerebral hemorrhage (ICH). This indicates that miR-23b may be closely related to the patho-physiological mechanism of ICH, but this hypothesis lacks direct evidence. In this study, we established rat models of ICH by injecting collagenase VII into the right basal ganglia and treating them with an injection of bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-23b via the tail vein. We found that edema in the rat brain was markedly reduced and rat behaviors were improved after BMSC exosomal miR-23b injection compared with those in the ICH groups. Additionally, exosomal miR-23b was transported to the microglia/macrophages, thereby reducing oxidative stress and pyroptosis after ICH. We also used hemin to mimic ICH conditions in vitro. We found that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was the downstream target gene of miR-23b, and exosomal miR-23b exhibited antioxidant effects by regulating the PTEN/Nrf2 pathway. Moreover, miR-23b reduced PTEN binding to NOD-like receptor family pyrin domain containing 3 (NLRP3) and NLRP3 inflammasome activation, thereby decreasing the NLRP3-dependent pyroptosis level. These findings suggest that BMSC-derived exosomal miR-23b exhibits antioxidant effects through inhibiting PTEN and alleviating NLRP3 inflammasome-mediated pyroptosis, thereby promoting neurologic function recovery in rats with ICH. 

Key words: bone marrow mesenchymal stem cells, exosomal miRNAs, intracerebral hemorrhage, miR-23b, neuroinflammation, NLRP3 inflammasome, Nrf2, oxidative stress, PTEN, pyroptosis