Exosomes from hypoxic urine-derived stem cells facilitate healing of diabetic wound by targeting SERPINE1 through miR-486-5p
Ming‐Hui Fan, Xiuzhen Zhang, Yanlin Jiang, Jin-Kui Pi, Jiye Zhang, Yueqi Zhang, Fei Xing, Huiqi Xie
Abstract
Vascular pathologies and injuries are important factors for the delayed wound healing in diabetes. Previous studies have demonstrated that hypoxic environments could induce formation of new blood vessels by regulating intercellular communication and cellular behaviors. In this study, we have enhanced the angiogenic potential of exosomes by subjecting urine-derived stem cells (USCs) to hypoxic preconditioning. To prolong the retention of exosomes at the wound site, we have also engineered a novel dECM hydrogel termed SISMA, which was modified from porcine small intestinal submucosa (SIS). For its rapid and controllable gelation kinetics, excellent biocompatibility, and exosome release capability, the SISMA hydrogel has proven to be a reliable delivery vehicle for exosomes. The hypoxia-induced exosomes-loaded hydrogel has promoted endothelial cell proliferation, migration, and tube formation. More importantly, as evidenced by significant in vivo vascular regeneration in the early stages post-injury, it has facilitated tissue repair. This may because miR-486–5p in H-exo inhibit SERPINE1 activity in endothelial cell. Additionally, miRNA sequencing analysis suggested that the underlying mechanism for enhanced angiogenesis may be associated with the activation of classical HIF-1α signaling pathway. In summary, our study has presented a novel non-invasive, cell-free therapeutic approach for accelerating diabetes wound healing and development of a practical and efficient exosomes delivery platform. • A novel mechanism of angiogenesis mediated by miR-486–5p targeting SERPINE1. • A new high-biosafety extracellular matrix hydrogel for in vivo delivery of exosomes. • We have conducted for the first time a comprehensive miRNA sequencing of exosomes from urine-derived stem cells under normoxic and hypoxic conditions. This provides a potential reference for using USC-derived exosomes to treat diabetic wounds and other diseases.