Exosomal HMGB1 derived from hypoxia-conditioned bone marrow mesenchymal stem cells increases angiogenesis via the JNK/HIF-1α pathway.

Mesenchymal stem cells (MSCs) have been described to induce angiogenesis in various tissues and have been utilized for the development of novel cell-based therapies. Increasing evidence suggests that MSCs execute their paracrine function via the secretion of exosomes, especially under hypoxic conditions. However, the mechanisms by which MSCs-derived exosomes secreted under hypoxia enhance angiogenesis still remain unclear. In order to study exosome physiology under hypoxic or normoxic conditions we isolated exosomes from bone marrow mesenchymal stem cells (BMSCs). Furthermore, we detected the uptake of exosomes by HUVEC cells by immunofluorescence staining. Additionally, we determined the effects of exosomes on cell viability, migration and tube formation in HUVECs by CCK-8, migration and tube formation assays, respectively. We examined the expression of key proteins related to exosome induced angiogenesis by BMSCs cultured under hypoxic conditions by western blot. Exosomes released by BMSCs cultured under hypoxic conditions enhanced cell proliferation, migration and angiogenesis of HUVEC cells. Hypoxia induced the expression of HMGB1 in BMSC-derived exosomes, and silencing of HMGB1 abolished the angiogenic effect in HUVEC cells. Furthermore, exosomal HMGB1 activated the JNK signaling pathway and induced HIF-1α/VEGF expression, consequently enhancing angiogenesis in HUVECs. Our data reveal that exosomal HMGB1 promotes angiogenesis via JNK/HIF-1α signaling. Therefore, BMSC exosomes derived under hypoxia may have potential for development of novel treatment strategies for angiogenesis-related diseases.