Circulation. 2004;109:1615-1622
Published online before print March 22, 2004, doi: 10.1161/01.CIR.0000124476.32871.E3
Published online before print March 22, 2004, doi: 10.1161/01.CIR.0000124476.32871.E3
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(Circulation. 2004;109:1615-1622.)
© 2004 American Heart Association, Inc.
Clinical Investigation and Reports |
Profoundly Reduced Neovascularization Capacity of Bone Marrow Mononuclear Cells Derived From Patients With Chronic Ischemic Heart Disease
From Molecular Cardiology, Department of Internal Medicine IV, and Hematology, Department of Internal Medicine III (H.M.), University of Frankfurt, Frankfurt, Germany.
Correspondence to Stefanie Dimmeler, PhD, Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. E-mail dimmeler{at}em.uni-frankfurt.de
Received July 21, 2003; de novo received October 13, 2003; revision received December 29, 2003; accepted January 5, 2004.
Background— Cell therapy with bone marrow–derived stem/progenitor cells is a novel option for improving neovascularization and cardiac function in ischemic heart disease. Circulating endothelial progenitor cells in patients with coronary heart disease are impaired with respect to number and functional activity. However, whether this impairment also extends to bone marrow–derived mononuclear cells (BM-MNCs) in patients with chronic ischemic cardiomyopathy (ICMP) is unclear.
Methods and Results— BM-MNCs were isolated from bone marrow aspirates in 18 patients with ICMP (ejection fraction, 38±11%) and 8 healthy control subjects (controls). The number of hematopoietic stem/progenitor cells (CD34+/CD133+), CD49d+ (VLA-4) cells, and CXCR4+ cells did not differ between the 2 groups. However, the colony-forming capacity of BM-MNCs from patients with ICMP was significantly lower compared with BM-MNCs from healthy controls (37.3±25.0 versus 113.8±70.4 granulocyte-macrophage colony-forming units; P=0.009). Likewise, the migratory response to stromal cell–derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) was significantly reduced in BM-MNCs derived from patients with ICMP compared with BM-MNCs from healthy controls (SDF-1, 46.3±26.2 versus 108.6±40.4 cells/microscopic field, P<0.001; VEGF, 34±24.2 versus 54.8±29.3 cells/microscopic field, P=0.027). To assess the in vivo relevance of these findings, we tested the functional activity of BM-MNCs to improve neovascularization in a hindlimb animal model using nude mice. Two weeks after ligation of the femoral artery and intravenous injection of 5x105 BM-MNCs, laser Doppler–derived relative limb blood flow in mice treated with BM-MNCs from patients with ICMP was significantly lower compared with mice treated with BM-MNCs from healthy controls (0.45±0.14 versus 0.68±0.15; P<0.001). The in vivo neovascularization capacity of BM-MNCs closely correlated with the in vitro assessment of SDF-1–induced migration (r=0.78; P<0.001) and colony-forming capacity (r=0.74; P<0.001).
Conclusions— BM-MNCs isolated from patients with ICMP have a significantly reduced migratory and colony-forming activity in vitro and a reduced neovascularization capacity in vivo despite similar content of hematopoietic stem cells. This functional impairment of BM-MNCs from patients with ICMP may limit their therapeutic potential for clinical cell therapy.
Key Words: stem cells • progenitor cells • angiogenesis • vasculogenesis • stromal cell–derived factor-1
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M. Valgimigli, G. M. Rigolin, A. Fucili, M. D. Porta, O. Soukhomovskaia, P. Malagutti, A. M. Bugli, L. Z. Bragotti, G. Francolini, E. Mauro, et al. CD34+ and Endothelial Progenitor Cells in Patients With Various Degrees of Congestive Heart Failure Circulation, September 7, 2004; 110(10): 1209 - 1212. [Abstract] [Full Text] [PDF]
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D. Perera, G. Kanaganayagam, and M. Marber Stem cells in unstable angina: the dynamic duo Eur. Heart J., June 2, 2004; 25(12): 999 - 1000. [Full Text] [PDF]
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