Published online before print February 1, 2007, doi: 10.1161/01.RES.0000259562.63718.35
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© 2007 American Heart Association, Inc.
Integrative Physiology |
Nonbone Marrow-Derived Circulating Progenitor Cells Contribute to Postnatal Neovascularization Following Tissue Ischemia
From the Department of Molecular Cardiology (A.A., K.S., S.D.), J.W. Goethe University, Frankfurt, Germany; Department of Surgery (M.R., C.H.), Ludwig-Maximilians-University, Munich, Germany; GSF, Institute at Molecular Immunology (J.W.E.), Munich, Germany; Department of General and Thoracic Surgery (F.F.) and Institute of Human Genetics (R.S.), University Hospital Schleswig-Holstein, Kiel, Germany; Division of Cardiovascular Medicine (J.P.C.), Stanford University School of Medicine, Calif.
Correspondence to Christopher Heeschen; Department of Surgery, Ludwig-Maximilians-University, Marchioninistr. 15, 81377 Munich, Germany. E-mail christopher.heeschen{at}med.uni-muenchen.de
Circulating progenitor cells home to sites of postnatal neovascularization and differentiate into endothelial cells but questions remain regarding the source of these cells. Indeed, a recent study suggests that nonbone marrow-derived cells may be even more important than bone marrow-derived cells in the setting of transplant arteriosclerosis. Thus, we aimed to thoroughly investigate the contribution of nonbone marrow-derived progenitor cells for neovascularization. We exclusively identified nonbone marrow-derived progenitor cells by combining a parabiosis model with reverse bone marrow transplantation followed by hindlimb ischemia. In this model, nonbone marrow-derived circulating progenitor cells attributed for 74±13% of the circulating progenitor cells that incorporated into the ischemic hindlimb. Increasing evidence suggests that organs such as small intestine and liver contain a considerable number of tissue resident progenitor cells and, thus, represent putative sources for nonbone marrow-derived progenitors. To track organ-derived progenitors, we transplanted sex-mismatched small intestine or liver, respectively, into rats followed by induction of hindlimb ischemia. These experiments show that organ-derived progenitor cells are contributing to postnatal vasculogenesis (intestine: 4.7±3.7%; liver: 6.3±2.2%). Based on the subsequent observation that liver-derived nonhematopoietic c-kit+CD45– progenitors are mobilized on induction of hindlimb ischemia, we prospectively isolated and intravenously infused these progenitors from murine livers. The isolated cells demonstrated a marked capacity for enhancing neovascularization and restoring blood flow to the ischemic hindlimb (no cells: 26.4±4.8% of normal blood flow; c-kit+CD45– cells: 67.0±8.0% of normal flow; P<0.01). In conclusion, we find that nonbone marrow-derived c-kit+CD45– progenitors contribute to postnatal neovascularization to an extent that is similar to that of bone marrow-derived progenitor cells. Intestine and liver represent a rich source for mobilized tissue-residing progenitor cells.
Key Words: angiogenesis • vasculogenesis • progenitor cells • stem cells • hindlimb ischemia • parabiosis
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