Exosomes secreted by hypoxic cardiosphere‐derived cells enhance tube formation and increase pro‐angiogenic miRNA

Exosomes are required for the regenerative effects of human cardiosphere‐derived cells (CDCs). Studies show that they mimic the cardioprotective benefits of CDCs in rodents and porcine myocardial infarction (MI) models. Hypoxic preconditioning of stem cells increases the cardioprotective effects of exosomes in MI models by enhancing angiogenesis. Several exosomal microRNAs (miRNAs) up‐regulate in response to hypoxia and play a role in cardioprotective and pro‐angiogenic effects. In this study, we have demonstrated that human CDCs secreted exosomes under hypoxic conditions (1% O2 for 2 days) enhanced tube formation by human umbilical vein endothelial cells (HUVECs) at a concentration of 25 µg/mL. Pro‐angiogenic exosomal miRNAs including miR‐126, miR‐130a, and miR‐210 showed a substantial increase (>2‐, >2‐, and >4‐fold, respectively) in the hypoxic exosomes compared to normoxic CDC‐derived exosomes. Our study suggested a significant benefit of hypoxic CDC exosomes for the treatment of cardiac diseases by induction of angiogenesis via enrichment of pro‐angiogenic exosomal miRNAs. Exosomes are required for the regenerative effects of CDCs. It was observed that hypoxic preconditioning increased the angiogenic effect of CDC exosomes. Moreover, hypoxic preconditioning of CDCs up‐regulated pro‐angiogenic exsosomal microRNAs.