Hypoxia Inducible Factor‐1α Potentiates Jagged 1‐Mediated Angiogenesis by Mesenchymal Stem Cell‐Derived Exosomes

Insufficient vessel growth associated with ischemia remains an unresolved issue in vascular medicine. Mesenchymal stem cells (MSCs) have been shown to promote angiogenesis via a mechanism that is potentiated by hypoxia. Overexpression of hypoxia inducible factor (HIF)‐1α in MSCs improves their therapeutic potential by inducing angiogenesis in transplanted tissues. Here, we studied the contribution of exosomes released by HIF‐1α‐overexpressing donor MSCs (HIF‐MSC) to angiogenesis by endothelial cells. Exosome secretion was enhanced in HIF‐MSC. Omics analysis of miRNAs and proteins incorporated into exosomes pointed to the Notch pathway as a candidate mediator of exosome communication. Interestingly, we found that Jagged1 was the sole Notch ligand packaged into MSC exosomes and was more abundant in HIF‐MSC than in MSC controls. The addition of Jagged1‐containing exosomes from MSC and HIF‐MSC cultures to endothelial cells triggered transcriptional changes in Notch target genes and induced angiogenesis in an in vitro model of capillary‐like tube formation, and both processes were stimulated by HIF‐1α. Finally, subcutaneous injection of Jagged 1‐containing exosomes from MSC and HIF‐MSC cultures in the Matrigel plug assay induced angiogenesis in vivo, which was more robust when they were derived from HIF‐MSC cultures. All Jagged1‐mediated effects could be blocked by prior incubation of exosomes with an anti‐Jagged 1 antibody. All together, the results indicate that exosomes derived from MSCs stably overexpressing HIF‐1α have an increased angiogenic capacity in part via an increase in the packaging of Jagged1, which could have potential applications for the treatment of ischemia‐related disease. S tem C ells 2017;35:1747–1759