The Wnt antagonist Dickkopf-1 mobilizes vasculogenic progenitor cells via activation of the bone marrow endosteal stem cell niche.
Therapeutic mobilization of vasculogenic progenitor cells is a novel strategy to enhance neovascularization for tissue repair. Prototypical mobilizing agents such as granulocyte colony-stimulating factor mobilize vasculogenic progenitor cells from the bone marrow concomitantly with inflammatory cells. In the bone marrow, mobilization is regulated in the stem cell niche, in which endosteal cells such as osteoblasts and osteoclasts play a key role. Because Wnt signaling regulates endosteal cells, we examined whether the Wnt signaling antagonist Dickkopf (Dkk)-1 is involved in the mobilization of vasculogenic progenitor cells. Using TOP-GAL transgenic mice to determine activation of beta-catenin, we demonstrate that Dkk-1 regulates endosteal cells in the bone marrow stem cell niche and subsequently mobilizes vasculogenic and hematopoietic progenitors cells without concomitant mobilization of inflammatory neutrophils. The mobilization of vasculogenic progenitors required the presence of functionally active osteoclasts, as demonstrated in PTPepsilon-deficient mice with defective osteoclast function. Mechanistically, Dkk-1 induced the osteoclast differentiation factor RANKL, which subsequently stimulated the release of the major bone-resorbing protease cathepsin K. Eventually, the Dkk-1-induced mobilization of bone marrow-derived vasculogenic progenitors enhanced neovascularization in Matrigel plugs. Thus, these data show that Dkk-1 is a mobilizer of vasculogenic progenitors but not of inflammatory cells, which could be of great clinical importance to enhance regenerative cell therapy.
Aicher
Alexandra
A
Department of Internal Medicine III, J.W. Goethe University, Frankfurt, Germany. aicher_a@yahoo.com
Kollet
Orit
O
Heeschen
Christopher
C
Liebner
Stefan
S
Urbich
Carmen
C
Ihling
Christian
C
Orlandi
Alessia
A
Lapidot
Tsvee
T
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000378:metabolism*; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen; D004338:Drug Combinations; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007797:Laminin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D010010:Osteoclasts / Q000201:enzymology / Q000378:metabolism*; D011509:Proteoglycans; D053245:RANK Ligand / Q000378:metabolism; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000201:enzymology / Q000378:metabolism*; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D004338:Drug Combinations; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D011509:Proteoglycans; D053245:RANK Ligand; D011994:Recombinant Proteins; C505689:Tnfsf11 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; C059485:matrigel; D016179:Granulocyte Colony-Stimulating Factor; D003094:Collagen; C098067:Ptpre protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D002403:Cathepsins; D056657:Cathepsin K; C534132:Ctsk protein, mouse