Bone morphogenetic proteins 2 and 4 are selectively expressed by late outgrowth endothelial progenitor cells and promote neoangiogenesis.
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.


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.


CONCLUSIONS
BMP2/4 are a marker of ECFCs and play a key role in ECFC commitment and outgrowth during neovascularization.
Smadja
David M
DM
Université Paris Descartes, Faculté de Pharmacie, INSERM UMRS 765, 4 Avenue de l'observatoire, F-75006 Paris, France.
Bièche
Ivan
I
Silvestre
Jean-Sébastien
JS
Germain
Stéphane
S
Cornet
Adeline
A
Laurendeau
Ingrid
I
Duong-Van-Huyen
Jean-Paul
JP
Emmerich
Joseph
J
Vidaud
Michel
M
Aiach
Martine
M
Gaussem
Pascale
P
D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics*; D002352:Carrier Proteins / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism* / Q000637:transplantation; D005312:Fetal Blood / Q000166:cytology; D015870:Gene Expression; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000473:pathology / Q000628:therapy; D007866:Leg / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000099176:Noggin Protein
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D000099176:Noggin Protein; C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse