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

Abstract

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. Stem Cells 2017;35:1747-1759.

How hypoxia regulate exosomes in ischemic diseases and cancer microenvironment?

“…Subcutaneous implantation of Matrigel containing HIF‐MSC‐derived exosomes (enriched in Jagged 1) indicated a significantly higher angiogenesis rate than those derived from control MSCs. As a conclusion, it was demonstrated that hypoxia can increase angiogenic capacity of MSCs through increased packaging of Jagged1 in their exosomes, and suggested as a potential treatment strategy for ischemia‐related diseases …”

Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell‐free therapy

“…Apart from activation of particular genes, overexpression of certain genes that are already present in MSCs also provides some benefits. For example, the hypoxia inducible factor-1α (HIF-1α) has been shown to have angiogenic functions and is present in MSCs [9]. Upon the overexpression of HIF-1α, Jagged1 was found to be more abundant in exosomes derived from the same MSCs, leading them to be pro-angiogenic as well.…”

Exosomes: The New Mediator of Peritoneal Membrane Function

“…Enhanced microvessel density and blood perfusion in ischemic tissues have been confirmed after exosomes treatment [67]. For example, Gonzalez et al showed that exosomes stably overexpressing hypoxia inducible factor-1α (HIF-1α) exhibit increased angiogenic capacity, in part through an increase in the packaging of Jagged1 [68]. This HIF-1α-based mechanism regulates MSCs-derived exosomes and exosomes-mediated angiogenesis [67].…”