title: Overexpression of hypoxia-inducible factor-1 alpha improves vasculogenesis-related functions of endothelial progenitor cells.
abstract: Postnatal vasculogenesis is mediated by mobilization of endothelial progenitor cells (EPCs) from bone marrow and homing to ischemic tissues. This feature emphasizes this cell type for cell-based therapies aiming at the improvement of neovascularization in tissue engineering applications and regenerative medicine. In animal models, it was demonstrated that implantation of EPCs from cord blood (cbEPCs) led to the formation of a complex functional neovasculature, whereas EPCs isolated from adult peripheral blood (pbEPCs) showed a limited vasculogenic potential, which may be attributed to age-related dysfunction. Recently, it was demonstrated that activation of hypoxia-inducible factor-1α (Hif-1α) improves cell functions of progenitor cells of mesenchymal and endothelial origin. Thus, we hypothesized that overexpression of Hif-1α may improve the vasculogenesis-related phenotype of pbEPCs. In the present study, we overexpressed Hif-1α in pbEPCs and cbEPCs by using recombinant adenoviruses and investigated effects on stem cell- and vasculogenesis-related cell parameters. Overexpression of Hif-1α enhanced proliferation, invasion, cell survival and in vitro capillary sprout formation of both EPC populations. Migration was increased in cbEPCs upon Hif-1α overexpression, but not in pbEPCs. Cellular senescence was decreased in pbEPCs, while remained in cbEPCs, which showed, as expected, intrinsically a dramatically lower senescent phenotype in relation to pbEPCs. Similarly, the colony-formation capacity was much higher in cbEPCs in comparison to pbEPCs and was further increased by Hif-1α overexpression, whereas Hif-1α transduction exerted no significant influence on colony formation of pbEPCs. In summary, our experiments illustrated multifarious effects of Hif-1α overexpression on stem cell and vasculogenic parameters. Therefore, Hif-1α overexpression may represent a therapeutic option to improve cellular functions of adult as well as postnatal EPCs.
authors.affiliation: Freiburg University Medical Center, Department of Plastic Surgery, Freiburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kütscher
authors.affiliation: Freiburg University Medical Center, Department of Plastic Surgery, Freiburg, Germany.
authors.forename: Florian M
authors.initials: FM
authors.lastname: Lampert
authors.affiliation: Freiburg University Medical Center, Department of Obstetrics and Gynecology, Freiburg, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Kunze
authors.affiliation: Freiburg University Medical Center, Department of Obstetrics and Gynecology, Freiburg, Germany.
authors.forename: Filiz
authors.initials: F
authors.lastname: Markfeld-Erol
authors.affiliation: Freiburg University Medical Center, Department of Plastic Surgery, Freiburg, Germany.
authors.forename: G Björn
authors.initials: GB
authors.lastname: Stark
authors.affiliation: Freiburg University Medical Center, Department of Plastic Surgery, Freiburg, Germany. Electronic address: guenter.finkenzeller@uniklinik-freiburg.de.
authors.forename: Günter
authors.initials: G
authors.lastname: Finkenzeller
mesh_terms: D000367:Age Factors; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D066026:Endothelial Progenitor Cells / Q000378:metabolism*; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: Angiogenesis; EPC; Hif-1alpha; Proliferation; Vasculogenesis