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(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

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