Intranasal delivery of hypoxia-preconditioned extracellular vesicles derived from BMSCs alleviates neuroinflammation and brain dysfunction in TBI

Le résumé fourni par la source

Traumatic brain injury (TBI) leads to secondary injuries, such as neuroinflammation and brain dysfunction, which is a critical challenge in clinical treatment. The use of bone marrow mesenchymal stem cells (BMSCs) is one of the potential strategies to treat TBI by alleviating inflammation, reducing neuronal loss, and promoting brain function recovery. Extracellular vesicles (EVs) released by BMSCs are regarded as an ideal alternative to cell therapy. This study showed that hypoxia significantly enhanced the release of EVs from BMSCs, and hypoxia- preconditioning (H-EVs) treatment significant effects on promoting microglial M2 polarization, improving endothelial cell activity, and inhibiting the formation of neutrophil extracellular traps, ultimately accelerating brain function recovery. Mechanistically, single-cell sequencing revealed a significant reduction in specificity protein 1 (SP1) expression and a change in the proportion of infiltrating inflammatory cell subsets in brain tissues after the H-EVs treatment. Hypoxia-preconditioning changed the miRNA microarray analysis results in H-EVs, such that miR-145-5p negatively regulated nuclear factor kappa-B (NF-κB) by targeting SP1, induced microglial M2 polarization, alleviated endothelial cell dysfunction, and promoted brain function recovery. Intranasal delivery of hypoxia-induced BMSC-EVs showed great potential in the treatment of secondary TBI and revealed a novel mechanism by which miR-145-5p regulates inflammatory response and intercellular communication by inhibiting the SP1/NF-κB axis. Hypoxic preconditioning enhances the secretory capacity of BMSCs for extracellular vesicles, thereby conferring a more potent anti-inflammatory effect. Intranasal H-EVs delivery significantly promotes the activation of M2 microglia after TBI, thereby alleviating the apoptosis of endothelial cells and neurons. This is the first study to show that H-EVs can regulate microglial polarization via the miR-145-5p/SP1/NF-κB pathway, alleviate endothelial cell dysfunction, inhibit the formation and recruitment of neutrophil extracellular traps in the brain injury areas, and promote the recovery of cortical cerebral blood flow. This is the first instance of using single-cell sequencing to reveal the differences between the H-EVs and normoxia-preconditioning (N-EVs) in TBI treatment. Behavioral experiments demonstrated that H-EVs treatment significantly improved the neurological and motor function recovery of TBI rats.

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