期刊
STEM CELLS
卷 35, 期 7, 页码 1747-1759出版社
WILEY
DOI: 10.1002/stem.2618
关键词
Mesenchymal stem cells; Exosomes; Hypoxia-inducible factor; Jagged 1; Angiogenesis
资金
- Institute de Salud Carlos III [PI13/00414, PI16/00107]
- RETICS [RD12/0019/0025, RD16/0011/0004]
- FEDER una manera de hacer Europa
- Regenerative Medicine Program of Institut de Salud Carlos III
- Valencian Community
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)-17 in MSCs improves their therapeutic potential by inducing angiogenesis in transplanted tissues. Here, we studied the contribution of exosomes released by HIF-1a-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 Jaggedl 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-17. 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 Jaggedl-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-17 have an increased angiogenic capacity in part via an increase in the packaging of Jaggedl, which could have potential applications for the treatment of ischemiarelated disease.
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