Schwann cells-derived exosomes facilitate revascularization via regulating endothelial metabolic reprogramming after peripheral nerve injury.

Abstract

Abstract Vascular reconstruction is indispensable for the regenerative microenvironment after peripheral nerve injury (PNI), while the intrinsic mechanisms remain unclear. Our study found a novel function of Schwann cell facilitating intraneural revascularization and a novel mechanism of miR-21-5p regulating energy metabolism of endothelia cells (ECs) in favor of glycolysis, and determines an important link among exosome, metabolism, angiogenesis, and nerve repair after peripheral nerve injury. Hypoxia-upregulated miR-21-5p in Schwann cells-derived exosomes targets von Hippel-Lindau/Hypoxia-inducible factor-1α (VHL/HIF-1α) pathway and pyruvate dehydrogenase-E1α subunit (PDH-E1α) at once to further skew ECs’ energy metabolism to glycolysis. Interestingly, HIF-1α inactivated PDH-E1α by activating PDK1 to restrain ECs’ oxidative phosphorylation (OXPHOS) finally enhancing glycolysis. Thus, the modulation of ECs’energic metabolism by SCs-Exos-derived miR-21-5p is crucial for intraneural revascularization and nerve regeneration in response to injury.