This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 28/12/2137    most recent ATVBAHA.108.168815v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Smadja, D. M. Articles by Gaussem, P. Search for Related Content PubMed PubMed Citation Articles by Smadja, D. M. Articles by Gaussem, P. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Stem Cells Related Collections Angiogenesis Peripheral vascular disease Other Vascular biology

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2137.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Bone Morphogenetic Proteins 2 and 4 Are Selectively Expressed by Late Outgrowth Endothelial Progenitor Cells and Promote Neoangiogenesis

David M. Smadja; Ivan Bièche; Jean-Sébastien Silvestre; Stéphane Germain; Adeline Cornet; Ingrid Laurendeau; Jean-Paul Duong-Van-Huyen; Joseph Emmerich; Michel Vidaud; Martine Aiach; Pascale Gaussem

From the Université Paris Descartes (D.M.S., I.B., I.L., J.-P.D.-V.-H., J.E., M.V., M.A., P.G.), Paris; Inserm UMRS 765 (D.M.S., A.C., J.E., M.A., P.G.), Faculté de Pharmacie; AP-HP (D.M.S., S.G., J.-P.D.-V.-H., J.E., M.A., P.G.), Hôpital Européen Georges Pompidou; Inserm UMRS 745 (I.B., I.L., M.V.), Faculté de Pharmacie; Inserm UMRS 689 (J.-S.S.), Centre de Recherche Cardiovasculaire Lariboisière; Inserm Unité 833 (S.G.), Paris; Collège de France, Experimental Medicine Unit (S.G.), Paris; and Inserm UMRS 872 (J.-P.D.-V.-H.), France.

Correspondence to Prof Pascale Gaussem, Université Paris Descartes, Faculté de Pharmacie, INSERM UMRS 765, 4 Avenue de l’observatoire, F-75006 Paris, France. E-mail pascale.gaussem{at}egp.aphp.fr

Objective— Endothelial progenitor cells are currently identified either by their surface antigen expression or by their generation of early colonies in culture (CFU-Hill). Another population, endothelial colony-forming cells (ECFCs), has strong vessel-forming capacity but is less well characterized. Given the potential usefulness of CFU-Hill and ECFCs as cell therapy products, their thorough characterization is of major importance.

Methods and Results— CFU-Hill and ECFCs were expanded from human cord and adult blood. Bone morphogenetic proteins 2 and 4 (BMP2/4) were selectively expressed by ECFCs but not by CFU-Hill. The BMP pathway was involved in ECFC commitment and angiogenic potential in vitro. In vivo, BMP inhibition strongly reduced plug vascularization in bFGF-containing Matrigel plugs implanted in C57/Bl6 mice. Moreover, ECFC exposure to BMP increased their therapeutic potential in a nude mouse model of hindlimb ischemia. In amputation specimens from patients with critical leg ischemia who had received a local therapeutic injection of bone marrow mononuclear cells, newly formed vessels were strongly positive for BMP2/4, suggesting that endothelial cells involved in neovascularization have an ECFC-like phenotype.

Conclusion— BMP2/4 are a marker of ECFCs and play a key role in ECFC commitment and outgrowth during neovascularization.

We report that bone morphogenetic proteins 2 and 4 (BMP2/4) are selectively expressed by ECFCs but not by CFU-Hill. The BMP pathway is involved in ECFC commitment and angiogenic potential. Newly formed vessels observed after BM-MNC injection in patients with critical leg ischemia were strongly positive for BMP2/4.

Key Words: endothelial progenitor cells • bone morphogenetic protein • critical leg ischemia • cell therapy • neovascularization

This article has been cited by other articles:

				M. Toshner, R. Voswinckel, M. Southwood, R. Al-Lamki, L. S. G. Howard, D. Marchesan, J. Yang, J. Suntharalingam, E. Soon, A. Exley, et al. Evidence of Dysfunction of Endothelial Progenitors in Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., October 15, 2009; 180(8): 780 - 787. [Abstract] [Full Text] [PDF]

				S.-H. Wang, S.-J. Lin, Y.-H. Chen, F.-Y. Lin, J.-C. Shih, C.-C. Wu, H.-L. Wu, and Y.-L. Chen Late Outgrowth Endothelial Cells Derived From Wharton Jelly in Human Umbilical Cord Reduce Neointimal Formation After Vascular Injury: Involvement of Pigment Epithelium-Derived Factor Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 816 - 822. [Abstract] [Full Text] [PDF]

				D. M. Smadja, P. Gaussem, L. Mauge, D. Israel-Biet, F. Dignat-George, S. Peyrard, G. Agnoletti, P. R. Vouhe, D. Bonnet, and M. Levy Circulating Endothelial Cells: A New Candidate Biomarker of Irreversible Pulmonary Hypertension Secondary to Congenital Heart Disease Circulation, January 27, 2009; 119(3): 374 - 381. [Abstract] [Full Text] [PDF]