Mesenchymal Stem Cell-Derived Mitochondrial Transfer Promotes Tip Cell Phenotype via Glutathione Metabolic Reprogramming in Stroke Mice

Angiogenesis is crucial to improving neurovascular remodeling poststroke. Therein, the transformation of endothelial cells (ECs) to tip cells is essential in initiating angiogenesis. Mitochondrial damage in ECs poststroke and associated metabolic disorder are key factors repressing angiogenesis, but the mechanisms are unknown. Here, we designed an Arg-Gly-Asp peptide (RGD)-modified, mitochondria-enriched, and extracellular vesicle mimetics (mitoEVMs) platform for mitochondrial transfer. RGD mediated the mesenchymal stem cell-derived mitochondria transfer to ECs around the lesion targetedly. We found MSC-derived mitochondria promoted tip cell transition and further stimulated angiogenesis after stroke, alleviated brain atrophy, and improved functional rehabilitation. We noticed mitochondrial transfer rescued mitochondrial function in ECs and reprogrammed glutathione metabolism to activate the mTORC1 pathway, upregulated the expression of p4E-BP1 and VEGFR2, and ultimately facilitated tip cell transition. Our work elucidates the mechanism of MSC-derived mitochondrial transfer in poststroke treatment and proposes a potential approach for rehabilitation after stroke.