title: 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.
authors.affiliation: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|Joint Unit for cardiovascular Repair Instituto de Investigación Sanitaria La Fe-Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Hernán
authors.initials: H
authors.lastname: Gonzalez-King
authors.affiliation: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|Joint Unit for cardiovascular Repair Instituto de Investigación Sanitaria La Fe-Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Nahuel A
authors.initials: NA
authors.lastname: García
authors.affiliation: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|Joint Unit for cardiovascular Repair Instituto de Investigación Sanitaria La Fe-Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Imelda
authors.initials: I
authors.lastname: Ontoria-Oviedo
authors.affiliation: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|Joint Unit for cardiovascular Repair Instituto de Investigación Sanitaria La Fe-Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Ciria
authors.affiliation: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|Joint Unit for cardiovascular Repair Instituto de Investigación Sanitaria La Fe-Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: José Anastasio
authors.initials: JA
authors.lastname: Montero
authors.affiliation: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|Joint Unit for cardiovascular Repair Instituto de Investigación Sanitaria La Fe-Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Pilar
authors.identifier: 0000-0001-6071-7431
authors.initials: P
authors.lastname: Sepúlveda
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015687:Cell Hypoxia; D018920:Coculture Techniques; D003782:Dental Pulp / Q000166:cytology / Q000378:metabolism; D055354:Exosomes / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D000072100:Jagged-1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic; D061251:Primary Cell Culture; D060149:Tetraspanin 30 / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D000097573:Red Fluorescent Protein
chemical_list: D057134:Antibodies, Neutralizing; D049452:Green Fluorescent Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000072100:Jagged-1 Protein; D008164:Luminescent Proteins; D060149:Tetraspanin 30; D000097573:Red Fluorescent Protein; C554586:CD63 protein, human; C497442:HIF1A protein, human
keywords: Angiogenesis; Exosomes; Hypoxia-inducible factor; Jagged 1; Mesenchymal stem cells