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Ischemic stroke is the second leading cause of death worldwide, in which ischemia-reperfusion injury (CIRI) plays a pivotal role in brain dysfunction and long-term disability. Extracellular vesicles (EVs) have recently been proven to be a promising therapeutic approach for CIRI. However, the mechanisms underlying the neuroprotective effects of EVs remain unclear. The group of Prof. Wang Fengshan and Prof. Zhang Xinke of the School of Pharmaceutical Sciences, Shandong University, recently published a groundbreaking study in Theranostics, entitled “MiR-125a-5p in extracellular vesicles of neural stem cells acts as a crosstalk signal modulating neuroinflammatory microenvironment to alleviate cerebral ischemia-reperfusion injury”.
This study identified and elucidated a novel regulatory network mediated by miR-125a-5p, which is delivered by neural stem cell-derived extracellular vesicles (hNSC-EVs). The network effectively modulates microglial polarization, neuronal repair, and the remodeling process after CIRI. These findings provide new theoretical foundations and potential therapeutic strategies for the treatment of CIRI.
The research demonstrated that the level of miR-125a-5p was markedly elevated in hNSC-EVs under hypoxic conditions. MiR-125a-5p in NSC-EVs plays a critical role through cell-to-cell signal transduction, particularly in the communication between microglia and neurons under ischemic conditions. MiR-125a-5p enriched hNSC-EVs (EVsmiR) significantly promote the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby mitigating inflammation and reducing the secretion of pro-inflammatory cytokines. Additionally, EVsmiR effectively suppresses neuronal death and substantially improves axonal ultrastructure and neurological function via multimodal MRI analysis. Further mechanistic studies revealed that EVsmiR exerts its neurorestorative effects by targeting IKBKG to regulate the TLR4/NF-κB signaling pathway.
This research highlights the pivotal role of miR-125a-5p in modulating the neuroinflammatory microenvironment, mediating intercellular communication, and orchestrating microglial polarization, neuronal repair, and tissue remodeling. It not only confirms the potential of miR-125a-5p-enriched hNSC-EVs as a novel therapeutic strategy for CIRI but also provides new perspectives for understanding the role of extracellular vesicles in intercellular communication and neural injury repair.
Prof. Wang Fengshan and Prof. Zhang Xinke of the School of Pharmaceutical Sciences at Shandong University serve as corresponding authors, and the Ph.D candidate, Liu Qingyue, is the first author of this article.
