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(Circulation Research. 2008;103:796.)
© 2008 American Heart Association, Inc.

Molecular Medicine

The Wnt Antagonist Dickkopf-1 Mobilizes Vasculogenic Progenitor Cells via Activation of the Bone Marrow Endosteal Stem Cell Niche

Alexandra Aicher, Orit Kollet, Christopher Heeschen, Stefan Liebner, Carmen Urbich, Christian Ihling, Alessia Orlandi, Tsvee Lapidot, Andreas M. Zeiher, Stefanie Dimmeler

From the Departments of Internal Medicine III (A.A., C.H., C.U., A.O., A.M.Z., S.D.) and Neurology (S.L.), J.W. Goethe University, Frankfurt, Germany; Weizmann Institute of Science (O.K., T.L.), Department of Immunology, Rehovot, Israel; and Pathology Associates (C.I.), Frankfurt, Germany.

Correspondence to Alexandra Aicher, MD, Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom. E-mail aicher_a{at}yahoo.com

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 β-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 PTP-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.

Key Words: Wnt signaling • angiogenesis • vasculogenesis • bone marrow microenvironment

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