中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (11): 3245-3258.doi: 10.4103/NRR.NRR-D-23-01144

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

人神经干细胞来源细胞外囊泡对缺血性脑卒中的神经保护

  

  • 出版日期:2025-11-15 发布日期:2025-02-25
  • 基金资助:
    该研究受国家自然科学基金(82072953、81471308)、辽宁省创新领军人才(XLYC1902031)、辽宁省科技项目(2022-BS-238)、辽宁省青年拔尖人才(XLYC1907009)、大连科技创新基金(2018J11CY025)资助

Human neural stem cell–derived extracellular vesicles protect against ischemic stroke by activating the PI3K/ AKT/mTOR pathway

Jiayi Wang1, 2, #, Mengke Zhao1, 2, #, Dong Fu2, 3, Meina Wang1, 2, Chao Han1, 2, Zhongyue Lv1, 2, Liang Wang1, 2, *, Jing Liu1, 2, *   

  1. 1 Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China;  2 Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning Province, China;  3 Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning Province, China
  • Online:2025-11-15 Published:2025-02-25
  • Contact: Jing Liu, PhD, liujing@dmu.edu.cn; Liang Wang, PhD, wangliang@dmu.edu.cn.
  • Supported by:
    This work was supported by the National Nature Science Foundation of China, No. 81471308 (to JL); the Innovative Leading Talents of Liaoning Province, No. XLYC1902031 (to JL); Science and Technology Projects in Liaoning Province, No. 2022-BS-238 (to CH); Young Top Talents of Liaoning Province, No. XLYC1907009 (to LW); and Dalian Science and Technology Innovation Fund, No. 2018J11CY025 (to JL).

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摘要：

人神经干细胞来源细胞外囊泡为开发治疗缺血性脑卒中的有效方法打开了新思路；然而，其有效性、安全性及确切机制仍然需要进一步的研究。此临床前研究发现，缺血性脑卒中大鼠模型右侧壳核移植人神经干细胞来源细胞外囊泡后，脑梗死体积明显缩小，神经细胞凋亡明显减少，神经功能恢复，且具有良好的体内安全性。人神经干细胞来源细胞外囊泡通过激活磷酸肌酸3-激酶（PI3K）、哺乳动物雷帕霉素靶标（mTOR）和蛋白激酶B（AKT）的磷酸化表达减少了神经元凋亡，而PI3K抑制剂可逆转磷酸肌酸3-激酶的磷酸化表达。以上数据表明，人神经干细胞来源细胞外囊泡通过激活PI3K/AKT/mTOR信号通路对缺血性脑卒中发挥神经保护作用，其有望成为治疗缺血性脑卒中的潜在策略。

https://orcid.org/0000-0002-0493-296X (Jing Liu); https://orcid.org/0000-0003-2244-7535 (Liang Wang)

Abstract: Human neural stem cell–derived extracellular vesicles exhibit analogous functions to their parental cells, and can thus be used as substitutes for stem cells in stem cell therapy, thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell–derived treatments. This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke. However, the precise mechanisms underlying the efficacy and safety of human neural stem cell–derived extracellular vesicles remain unclear, presenting challenges for clinical translation. To promote the translation of therapy based on human neural stem cell–derived extracellular vesicles from the bench to the bedside, we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell–derived extracellular vesicles in the treatment of ischemic stroke. We found that administration of human neural stem cell– derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis. The human neural stem cell–derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase, mammalian target of rapamycin, and protein kinase B, and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor. These findings suggest that human neural stem cell–derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Finally, we showed that human neural stem cell–derived extracellular vesicles have a good in vivo safety profile. Therefore, human neural stem cell–derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.

Key words: behavior, exosome, extracellular vesicles, ischemic stroke, mammalian target of rapamycin (mTOR), middle cerebral artery occlusion, neural stem cells, neuronal apoptosis, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT)