title: In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells.
abstract: Many stem cell types have been shown to differentiate into endothelial cells (ECs); however, their specification to arterial or venous endothelium remains unexplored. We tested whether a specific arterial or venous EC fate could be induced in human multipotent adult progenitor cells (hMAPCs) and AC133(+) cells (hAC133(+)). In vitro, in the presence of VEGF(165), hAC133(+) cells only adopted a venous and microvascular EC phenotype, while hMAPCs differentiated into both arterial and venous ECs, possibly because hMAPCs expressed significantly more sonic hedgehog (Shh) and its receptors as well as Notch 1 and 3 receptors and some of their ligands. Accordingly, blocking either of those pathways attenuated in vitro arterial EC differentiation from hMAPCs. Complementarily, stimulating these pathways by addition of Delta-like 4 (Dll-4), a Notch ligand, and Shh to VEGF(165) further boosted arterial differentiation in hMAPCs both in vitro and in an in vivo Matrigel model. These results represent the first demonstration of adult stem cells with the potential to be differentiated into different types of ECs in vitro and in vivo and provide a useful human model to study arteriovenous specification.
authors.affiliation: Hematology Service and Cell Therapy, Clínica Universitaria, Foundation for Applied Medical Research, Division of Cancer, University of Navarra, Pamplona, Spain.
authors.forename: Xabier L
authors.initials: XL
authors.lastname: Aranguren
authors.forename: Aernout
authors.initials: A
authors.lastname: Luttun
authors.forename: Carlos
authors.initials: C
authors.lastname: Clavel
authors.forename: Cristina
authors.initials: C
authors.lastname: Moreno
authors.forename: Gloria
authors.initials: G
authors.lastname: Abizanda
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Barajas
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pelacho
authors.forename: Maialen
authors.initials: M
authors.lastname: Uriz
authors.forename: Miriam
authors.initials: M
authors.lastname: Araña
authors.forename: Ana
authors.initials: A
authors.lastname: Echavarri
authors.forename: Mario
authors.initials: M
authors.lastname: Soriano
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Andreu
authors.forename: Juana
authors.initials: J
authors.lastname: Merino
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Garcia-Verdugo
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Verfaillie
authors.forename: Felipe
authors.initials: F
authors.lastname: Prósper
mesh_terms: D000071916:AC133 Antigen; D053687:Adult Stem Cells / Q000166:cytology* / Q000187:drug effects; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008854:Microscopy, Electron; D018919:Neovascularization, Physiologic; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D053823:Hedgehog Proteins; C000606023:PROM1 protein, human; D010446:Peptide Fragments; D010455:Peptides; C000606024:Prom1 protein, mouse; D051880:Receptors, Notch; C509239:SHH protein, human; D042461:Vascular Endothelial Growth Factor A