Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (11): 3245-3258.doi: 10.4103/NRR.NRR-D-23-01144

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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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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)