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Circulation. 2003;108:2511-2516
Published online before print October 27, 2003, doi: 10.1161/01.CIR.0000096483.29777.50
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(Circulation. 2003;108:2511.)
© 2003 American Heart Association, Inc.


Basic Science Reports

Relevance of Monocytic Features for Neovascularization Capacity of Circulating Endothelial Progenitor Cells

Carmen Urbich, PhD*; Christopher Heeschen, MD*; Alexandra Aicher, MD; Elisabeth Dernbach, MD; Andreas M. Zeiher, MD; Stefanie Dimmeler, PhD

From Molecular Cardiology, Department of Internal Medicine IV, University of 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 April 15, 2003; de novo received July 3, 2003; revision received July 22, 2003; accepted July 22, 2003.

Background— Transplantation of ex vivo expanded circulating endothelial progenitor cells (EPCs) from peripheral blood mononuclear cells improves the neovascularization after critical ischemia. However, the origin of the endothelial progenitor lineage and its characteristics have not yet been clearly defined. Therefore, we investigated whether the phenotype and functional capacity of EPCs to improve neovascularization depend on their monocytic origin.

Methods and Results— Monocytic CD14+ cells were isolated from mononuclear cells and incubated on fibronectin-coated dishes in endothelial medium in the presence of vascular endothelial growth factor. After 4 days of cultivation, adherent cells deriving from CD14+ or CD14- mononuclear cells showed equal expression of endothelial marker proteins and capacity for clonal expansion as determined by measuring endothelial colony-forming units. In addition, transplanted EPCs (5x105 cells) deriving from CD14+ or CD14- cells were incorporated into vascular structures of nude mice after hind-limb ischemia and significantly improved neovascularization from 0.27±0.12 (no cells) to 0.66±0.12 and 0.65±0.17, respectively (P<0.001; laser Doppler-derived relative blood flow). In contrast, no functional improvement of neovascularization was detected when freshly isolated CD14+ mononuclear cells without ex vivo expansion were used (0.33±0.17). Moreover, macrophages or dendritic cells differentiated from isolated CD14+ cells were significantly less effective in improving neovascularization than EPCs cultivated from the same starting population (P<0.01).

Conclusions— These data demonstrate that EPCs can be generated from nonmonocytic CD14- peripheral blood mononuclear cells and exhibit a unique functional activity to improve neovascularization after hind-limb ischemia.


Key Words: angiogenesis • endothelium • cells




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BloodHome page
D. A. Ingram, N. M. Caplice, and M. C. Yoder
Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells
Blood, September 1, 2005; 106(5): 1525 - 1531.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
C. Liu, S. Wang, A. Deb, K. A. Nath, Z. S. Katusic, J. P. McConnell, and N. M. Caplice
Proapoptotic, Antimigratory, Antiproliferative, and Antiangiogenic Effects of Commercial C-Reactive Protein on Various Human Endothelial Cell Types In Vitro: Implications of Contaminating Presence of Sodium Azide in Commercial Preparation
Circ. Res., July 22, 2005; 97(2): 135 - 143.
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HypertensionHome page
V. J. Dzau, M. Gnecchi, A. S. Pachori, F. Morello, and L. G. Melo
Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases
Hypertension, July 1, 2005; 46(1): 7 - 18.
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CirculationHome page
C. Schmidt-Lucke, L. Rossig, S. Fichtlscherer, M. Vasa, M. Britten, U. Kamper, S. Dimmeler, and A. M. Zeiher
Reduced Number of Circulating Endothelial Progenitor Cells Predicts Future Cardiovascular Events: Proof of Concept for the Clinical Importance of Endogenous Vascular Repair
Circulation, June 7, 2005; 111(22): 2981 - 2987.
[Abstract] [Full Text] [PDF]


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JEMHome page
L. Rossig, C. Urbich, T. Bruhl, E. Dernbach, C. Heeschen, E. Chavakis, K.-i. Sasaki, D. Aicher, F. Diehl, F. Seeger, et al.
Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells
J. Exp. Med., June 6, 2005; 201(11): 1825 - 1835.
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Eur Heart JHome page
A. M. Leone, S. Rutella, G. Bonanno, A. Abbate, A. G. Rebuzzi, S. Giovannini, M. Lombardi, L. Galiuto, G. Liuzzo, F. Andreotti, et al.
Mobilization of bone marrow-derived stem cells after myocardial infarction and left ventricular function
Eur. Heart J., June 2, 2005; 26(12): 1196 - 1204.
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CirculationHome page
B. Modarai, K.G. Burnand, B. Sawyer, and A. Smith
Endothelial Progenitor Cells Are Recruited Into Resolving Venous Thrombi
Circulation, May 24, 2005; 111(20): 2645 - 2653.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
H. Uchimura, T. Marumo, O. Takase, H. Kawachi, F. Shimizu, M. Hayashi, T. Saruta, K. Hishikawa, and T. Fujita
Intrarenal Injection of Bone Marrow-Derived Angiogenic Cells Reduces Endothelial Injury and Mesangial Cell Activation in Experimental Glomerulonephritis
J. Am. Soc. Nephrol., April 1, 2005; 16(4): 997 - 1004.
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HypertensionHome page
F. H. Bahlmann, K. de Groot, O. Mueller, B. Hertel, H. Haller, and D. Fliser
Stimulation of Endothelial Progenitor Cells: A New Putative Therapeutic Effect of Angiotensin II Receptor Antagonists
Hypertension, April 1, 2005; 45(4): 526 - 529.
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J. Clin. Endocrinol. Metab.Home page
J. Sugawara, M. Mitsui-Saito, T. Hoshiai, C. Hayashi, Y. Kimura, and K. Okamura
Circulating Endothelial Progenitor Cells during Human Pregnancy
J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1845 - 1848.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
V. Schachinger and A. M. Zeiher
Stem Cells and Cardiovascular and Renal Disease: Today and Tomorrow
J. Am. Soc. Nephrol., March 1, 2005; 16(3_suppl_1): S2 - S6.
[Abstract] [Full Text] [PDF]


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HypertensionHome page
A. Aicher, A. M. Zeiher, and S. Dimmeler
Mobilizing Endothelial Progenitor Cells
Hypertension, March 1, 2005; 45(3): 321 - 325.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
T. M. Powell, J. D. Paul, J. M. Hill, M. Thompson, M. Benjamin, M. Rodrigo, J. P. McCoy, E. J. Read, H. M. Khuu, S. F. Leitman, et al.
Granulocyte Colony-Stimulating Factor Mobilizes Functional Endothelial Progenitor Cells in Patients With Coronary Artery Disease
Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 296 - 301.
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BloodHome page
J. R. Conejo-Garcia, R. J. Buckanovich, F. Benencia, M. C. Courreges, S. C. Rubin, R. G. Carroll, and G. Coukos
Vascular leukocytes contribute to tumor vascularization
Blood, January 15, 2005; 105(2): 679 - 681.
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JEMHome page
E. Chavakis, A. Aicher, C. Heeschen, K.-i. Sasaki, R. Kaiser, N. El Makhfi, C. Urbich, T. Peters, K. Scharffetter-Kochanek, A. M. Zeiher, et al.
Role of {beta}2-integrins for homing and neovascularization capacity of endothelial progenitor cells
J. Exp. Med., January 3, 2005; 201(1): 63 - 72.
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CirculationHome page
G. Nowak, A. Karrar, C. Holmen, S. Nava, M. Uzunel, K. Hultenby, and S. Sumitran-Holgersson
Expression of Vascular Endothelial Growth Factor Receptor-2 or Tie-2 on Peripheral Blood Cells Defines Functionally Competent Cell Populations Capable of Reendothelialization
Circulation, December 14, 2004; 110(24): 3699 - 3707.
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Nephrol Dial TransplantHome page
D. Fliser, K. de Groot, F. H. Bahlmann, and H. Haller
Cardiovascular disease in renal patients--a matter of stem cells?
Nephrol. Dial. Transplant., December 1, 2004; 19(12): 2952 - 2954.
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BloodHome page
E. De Falco, D. Porcelli, A. R. Torella, S. Straino, M. G. Iachininoto, A. Orlandi, S. Truffa, P. Biglioli, M. Napolitano, M. C. Capogrossi, et al.
SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells
Blood, December 1, 2004; 104(12): 3472 - 3482.
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BloodHome page
E. Dernbach, C. Urbich, R. P. Brandes, W. K. Hofmann, A. M. Zeiher, and S. Dimmeler
Antioxidative stress-associated genes in circulating progenitor cells: evidence for enhanced resistance against oxidative stress
Blood, December 1, 2004; 104(12): 3591 - 3597.
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CirculationHome page
I. Spyridopoulos, J. Haendeler, C. Urbich, T. H. Brummendorf, H. Oh, M. D. Schneider, A. M. Zeiher, and S. Dimmeler
Statins Enhance Migratory Capacity by Upregulation of the Telomere Repeat-Binding Factor TRF2 in Endothelial Progenitor Cells
Circulation, November 9, 2004; 110(19): 3136 - 3142.
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Arterioscler. Thromb. Vasc. Bio.Home page
L. Rossig, C. Urbich, and S. Dimmeler
Endothelial Progenitor Cells at Work: Not Mature Yet, but Already Stress-Resistant
Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 1977 - 1979.
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BloodHome page
I. Rajantie, M. Ilmonen, A. Alminaite, U. Ozerdem, K. Alitalo, and P. Salven
Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells
Blood, October 1, 2004; 104(7): 2084 - 2086.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
C. Urbich and S. Dimmeler
Endothelial Progenitor Cells: Characterization and Role in Vascular Biology
Circ. Res., August 20, 2004; 95(4): 343 - 353.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
K. L. March and B. H. Johnstone
Cellular approaches to tissue repair in cardiovascular disease: the more we know, the more there is to learn
Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H458 - H463.
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Arterioscler. Thromb. Vasc. Bio.Home page
T. Kondo, M. Hayashi, K. Takeshita, Y. Numaguchi, K. Kobayashi, S. Iino, Y. Inden, and T. Murohara
Smoking Cessation Rapidly Increases Circulating Progenitor Cells in Peripheral Blood in Chronic Smokers
Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1442 - 1447.
[Abstract] [Full Text] [PDF]


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Nephrol Dial TransplantHome page
J. Honold, B. Assmus, R. Lehman, A. M. Zeiher, and S. Dimmeler
Stem cell therapy of cardiac disease: an update
Nephrol. Dial. Transplant., July 1, 2004; 19(7): 1673 - 1677.
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CirculationHome page
D. W. Losordo and S. Dimmeler
Therapeutic Angiogenesis and Vasculogenesis for Ischemic Disease: Part II: Cell-Based Therapies
Circulation, June 8, 2004; 109(22): 2692 - 2697.
[Full Text] [PDF]