Hypoxic bone marrow mesenchymal stem cell-derived exosomes promote neurovascular repair in ischemic stroke with CXCR4-Associated enhancement.

BACKGROUND: Ischemic stroke is a leading cause of disability and mortality worldwide, with limited therapeutic options for long-term recovery. Bone marrow-derived mesenchymal stem cell (BMSC)-derived exosomes have emerged as a promising cell-free therapy, but their efficacy is often constrained by poor homing efficiency. METHODS: Hypoxic preconditioning and silencing CXCR4 was done through genetic modification of rat BMSCs. The exosomes were captured and identified through transmission electron microscopy, nanoparticle tracking and western blot. The middle cerebral artery occlusion (MCAO) rat model was established and animals were treated with exosomes derived from normoxic, hypoxic, and CXCR4-ooverexpressed or knock-downed BMSCs. Neurological function, infarct volume, vascular density, apoptosis, and neuroinflammation were assessed through behavioral tests, TTC staining, immunofluorescence, and TUNEL assays. RESULTS: Hypoxic preconditioning significantly enhanced the therapeutic effects of BMSC-derived exosomes, as evidenced by improved neurological scores, reduced infarct volume, and increased cerebral microvascular perfusion. CXCR4 overexpression further enhanced these hypoxia-associated benefits, whereas CXCR4 knockdown partially attenuated them, suggesting that CXCR4 contributes to the therapeutic effects of hypoxic BMSC-derived exosomes. CONCLUSION: Hypoxic BMSC-derived exosomes promote neurovascular repair after ischemic stroke, and CXCR4 appears to be an important contributing factor that enhances these therapeutic effects.