In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells
Xabier L. Aranguren (1), Aernout Luttun (2,3), Carlos Clavel (1), Cristina Moreno (1,4), Gloria Abizanda(1), Miguel A. Barajas (1,2), Beatriz Pelacho (2), Maialen Uriz (1), Miriam Araña (1), Ana Echavarri (1), Mario Soriano (5), Enrique J. Andreu (1), Juana Merino (4), Jose Manuel Garcia-Verdugo (5), Catherine M. Verfaillie (2), and Felipe Prósper (1)
(1) Hematology Service and Cell Therapy, Clínica Universitaria, Foundation for Applied Medical Research, Division of Cancer, University of Navarra, Pamplona, Spain
(2) Stem Cell Institute, University of Minnesota Medical School, Minneapolis
(3) Center for Molecular and Vascular Biology, Catholic University of Leuven, Belgium
(4) Immunology Service, Clínica Universitaria, University of Navarra, Pamplona, Spain
(5) Department of Cell Biology, Instituto Cavanilles, University of Valencia, Spain
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.
CITATION Blood. 2007 Mar 15;109(6):2634-42