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Blood, Vol. 95 No. 3 (February 1), 2000: pp. 952-958

Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors

Mario Peichev, Afzal J. Naiyer, Daniel Pereira, Zhenping Zhu, William J. Lane, Mathew Williams, Mehmet C. Oz, Daniel J. Hicklin, Larry Witte, Malcolm A. S. Moore, and Shahin Rafii

From the Division of Hematology-Oncology, Weill Medical College of Cornell University, New York, NY; Division of Molecular, Cell Biology and Immunology, ImClone Systems, New York, NY; Department of Cardiothoracic Surgery, Columbia-Presbyterian Medical Center, New York, NY; and Division of Developmental Hematopoiesis, Sloan Kettering Cancer Center, New York, NY.

Emerging data suggest that a subset of circulating human CD34+ cells have phenotypic features of endothelial cells. Whether these cells are sloughed mature endothelial cells or functional circulating endothelial precursors (CEPs) is not known. Using monoclonal antibodies (MoAbs) to the extracellular domain of the human vascular endothelial receptor-2 (VEGFR-2), we have shown that 1.2 ± 0.3% of CD34+ cells isolated from fetal liver (FL), 2 ± 0.5% from mobilized peripheral blood, and 1.4 ± 0.5% from cord blood were VEGFR-2+. In addition, most CD34+VEGFR-2+ cells express hematopoietic stem cell marker AC133. Because mature endothelial cells do not express AC133, coexpression of VEGFR-2 and AC133 on CD34+ cells phenotypically identifies a unique population of CEPs. CD34+VEGFR-2+ cells express endothelial-specific markers, including VE-cadherin and E-selectin. Also, virtually all CD34+VEGFR-2+ cells express the chemokine receptor CXCR4 and migrate in response to stromal-derived factor (SDF)-1 or VEGF. To quantitate the plating efficiency of CD34+ cells that give rise to endothelial colonies, CD34+ cells derived from FL were incubated with VEGF and fibroblast growth factor (FGF)-2. Subsequent isolation and plating of nonadherent FL-derived VEGFR-2+ cells with VEGF and FGF-2 resulted in differentiation of AC133+ VEGFR-2+ cells into adherent AC133-VEGFR-2+Ac-LDL+ (acetylated low-density lipoprotein) colonies (plating efficiency of 3%). In an in vivo human model, we have found that the neo-intima formed on the surface of left ventricular assist devices is colonized with AC133+VEGFR-2+ cells. These data suggest that circulating CD34+ cells expressing VEGFR-2 and AC133 constitute a phenotypically and functionally distinct population of circulating endothelial cells that may play a role in neo-angiogenesis.


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BloodHome page
M. Nagano, T. Yamashita, H. Hamada, K. Ohneda, K.-i. Kimura, T. Nakagawa, M. Shibuya, H. Yoshikawa, and O. Ohneda
Identification of functional endothelial progenitor cells suitable for the treatment of ischemic tissue using human umbilical cord blood
Blood, July 1, 2007; 110(1): 151 - 160.
[Abstract] [Full Text] [PDF]


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J Am Coll CardiolHome page
C. K. Kissel, R. Lehmann, B. Assmus, A. Aicher, J. Honold, U. Fischer-Rasokat, C. Heeschen, I. Spyridopoulos, S. Dimmeler, and A. M. Zeiher
Selective Functional Exhaustion of Hematopoietic Progenitor Cells in the Bone Marrow of Patients With Postinfarction Heart Failure
J. Am. Coll. Cardiol., June 19, 2007; 49(24): 2341 - 2349.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
C. V. Pfenninger, T. Roschupkina, F. Hertwig, D. Kottwitz, E. Englund, J. Bengzon, S. E. Jacobsen, and U. A. Nuber
CD133 Is Not Present on Neurogenic Astrocytes in the Adult Subventricular Zone, but on Embryonic Neural Stem Cells, Ependymal Cells, and Glioblastoma Cells
Cancer Res., June 15, 2007; 67(12): 5727 - 5736.
[Abstract] [Full Text] [PDF]


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Genes Dev.Home page
D. J. Nolan, A. Ciarrocchi, A. S. Mellick, J. S. Jaggi, K. Bambino, S. Gupta, E. Heikamp, M. R. McDevitt, D. A. Scheinberg, R. Benezra, et al.
Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization
Genes & Dev., June 15, 2007; 21(12): 1546 - 1558.
[Abstract] [Full Text] [PDF]


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J. Leukoc. Biol.Home page
L. Bezuidenhout, M. Bracher, G. Davison, P. Zilla, and N. Davies
Ang-2 and PDGF-BB cooperatively stimulate human peripheral blood monocyte fibrinolysis
J. Leukoc. Biol., June 1, 2007; 81(6): 1496 - 1503.
[Abstract] [Full Text] [PDF]


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Am. J. Pathol.Home page
G. Invernici, C. Emanueli, P. Madeddu, S. Cristini, S. Gadau, A. Benetti, E. Ciusani, G. Stassi, M. Siragusa, R. Nicosia, et al.
Human Fetal Aorta Contains Vascular Progenitor Cells Capable of Inducing Vasculogenesis, Angiogenesis, and Myogenesis in Vitro and in a Murine Model of Peripheral Ischemia
Am. J. Pathol., June 1, 2007; 170(6): 1879 - 1892.
[Abstract] [Full Text] [PDF]


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BloodHome page
J. M. Melero-Martin, Z. A. Khan, A. Picard, X. Wu, S. Paruchuri, and J. Bischoff
In vivo vasculogenic potential of human blood-derived endothelial progenitor cells
Blood, June 1, 2007; 109(11): 4761 - 4768.
[Abstract] [Full Text] [PDF]


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BloodHome page
P. Dentelli, A. Rosso, A. Balsamo, S. Colmenares Benedetto, A. Zeoli, M. Pegoraro, G. Camussi, L. Pegoraro, and M. F. Brizzi
C-KIT, by interacting with the membrane-bound ligand, recruits endothelial progenitor cells to inflamed endothelium
Blood, May 15, 2007; 109(10): 4264 - 4271.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
A. V. R. Santhanam, L. A. Smith, T. He, K. A. Nath, and Z. S. Katusic
Endothelial Progenitor Cells Stimulate Cerebrovascular Production of Prostacyclin By Paracrine Activation of Cyclooxygenase-2
Circ. Res., May 11, 2007; 100(9): 1379 - 1388.
[Abstract] [Full Text] [PDF]


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Eur Heart JHome page
H. D. Theiss, R. David, M. G. Engelmann, A. Barth, K. Schotten, M. Naebauer, B. Reichart, G. Steinbeck, and W.-M. Franz
Circulation of CD34+ progenitor cell populations in patients with idiopathic dilated and ischaemic cardiomyopathy (DCM and ICM)
Eur. Heart J., May 2, 2007; 28(10): 1258 - 1264.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
S. Schwartzenberg, V. Deutsch, S. Maysel-Auslender, S. Kissil, G. Keren, and J. George
Circulating Apoptotic Progenitor Cells: A Novel Biomarker in Patients With Acute Coronary Syndromes
Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): e27 - e31.
[Abstract] [Full Text] [PDF]


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Clin. Cancer Res.Home page
A. Norden-Zfoni, J. Desai, J. Manola, P. Beaudry, J. Force, R. Maki, J. Folkman, C. Bello, C. Baum, S. E. DePrimo, et al.
Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor
Clin. Cancer Res., May 1, 2007; 13(9): 2643 - 2650.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
V. Balasubramaniam, C. F. Mervis, A. M. Maxey, N. E. Markham, and S. H. Abman
Hyperoxia reduces bone marrow, circulating, and lung endothelial progenitor cells in the developing lung: implications for the pathogenesis of bronchopulmonary dysplasia
Am J Physiol Lung Cell Mol Physiol, May 1, 2007; 292(5): L1073 - L1084.
[Abstract] [Full Text] [PDF]


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Stem CellsHome page
Y. Yamada, S.-i. Yokoyama, X.-D. Wang, N. Fukuda, and N. Takakura
Cardiac Stem Cells in Brown Adipose Tissue Express CD133 and Induce Bone Marrow Nonhematopoietic Cells to Differentiate into Cardiomyocytes
Stem Cells, May 1, 2007; 25(5): 1326 - 1333.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
V. L.T. Ballard and J. M. Edelberg
Stem Cells and the Regeneration of the Aging Cardiovascular System
Circ. Res., April 27, 2007; 100(8): 1116 - 1127.
[Abstract] [Full Text] [PDF]


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DiabetesHome page
S. Caballero, N. Sengupta, A. Afzal, K.-H. Chang, S. Li Calzi, D. L. Guberski, T. S. Kern, and M. B. Grant
Ischemic Vascular Damage Can Be Repaired by Healthy, but Not Diabetic, Endothelial Progenitor Cells
Diabetes, April 1, 2007; 56(4): 960 - 967.
[Abstract] [Full Text] [PDF]


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haematolHome page
C. Igreja, M. Courinha, A. S. Cachaco, T. Pereira, J. Cabecadas, M. G. da Silva, and S. Dias
Characterization and clinical relevance of circulating and biopsy-derived endothelial progenitor cells in lymphoma patients
Haematologica, April 1, 2007; 92(4): 469 - 477.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
C. Murphy, G. S. Kanaganayagam, B. Jiang, P. J. Chowienczyk, R. Zbinden, M. Saha, S. Rahman, A. M. Shah, M. S. Marber, and M. T. Kearney
Vascular Dysfunction and Reduced Circulating Endothelial Progenitor Cells in Young Healthy UK South Asian Men
Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 936 - 942.
[Abstract] [Full Text] [PDF]


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J BiochemHome page
A. Casamassimi, M. L. Balestrieri, C. Fiorito, C. Schiano, C. Maione, R. Rossiello, V. Grimaldi, V. Del Giudice, C. Balestrieri, B. Farzati, et al.
Comparison Between Total Endothelial Progenitor Cell Isolation Versus Enriched Cd133+ Culture
J. Biochem., April 1, 2007; 141(4): 503 - 511.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
P. Madeddu and C. Emanueli
Switching on Reparative Angiogenesis: Essential Role of the Vascular Erythropoietin Receptor
Circ. Res., March 16, 2007; 100(5): 599 - 601.
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Circ. Res.Home page
M. Hristov, A. Zernecke, K. Bidzhekov, E. A. Liehn, E. Shagdarsuren, A. Ludwig, and C. Weber
Importance of CXC Chemokine Receptor 2 in the Homing of Human Peripheral Blood Endothelial Progenitor Cells to Sites of Arterial Injury
Circ. Res., March 2, 2007; 100(4): 590 - 597.
[Abstract] [Full Text] [PDF]


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J. Appl. Physiol.Home page
G. L. Hoetzer, G. P. Van Guilder, H. M. Irmiger, R. S. Keith, B. L. Stauffer, and C. A. DeSouza
Aging, exercise, and endothelial progenitor cell clonogenic and migratory capacity in men
J Appl Physiol, March 1, 2007; 102(3): 847 - 852.
[Abstract] [Full Text] [PDF]


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BloodHome page
M. C. Yoder, L. E. Mead, D. Prater, T. R. Krier, K. N. Mroueh, F. Li, R. Krasich, C. J. Temm, J. T. Prchal, and D. A. Ingram
Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals
Blood, March 1, 2007; 109(5): 1801 - 1809.
[Abstract] [Full Text] [PDF]


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Stem CellsHome page
T. Chen, H. Bai, Y. Shao, M. Arzigian, V. Janzen, E. Attar, Y. Xie, D. T. Scadden, and Z. Z. Wang
Stromal Cell-Derived Factor-1/CXCR4 Signaling Modifies the Capillary-Like Organization of Human Embryonic Stem Cell-Derived Endothelium In Vitro
Stem Cells, February 1, 2007; 25(2): 392 - 401.
[Abstract] [Full Text] [PDF]


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ReproductionHome page
A. O Robb, N. L Mills, D. E Newby, and F. C Denison
Endothelial progenitor cells in pregnancy
Reproduction, January 1, 2007; 133(1): 1 - 9.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
G. C. Schatteman, M. Dunnwald, and C. Jiao
Biology of bone marrow-derived endothelial cell precursors
Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H1 - H18.
[Abstract] [Full Text] [PDF]


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J. Thorac. Cardiovasc. Surg.Home page
N. Bonaros, R. Rauf, D. Wolf, E. Margreiter, A. Tzankov, B. Schlechta, A. Kocher, H. Ott, T. Schachner, S. Hering, et al.
Combined transplantation of skeletal myoblasts and angiopoietic progenitor cells reduces infarct size and apoptosis and improves cardiac function in chronic ischemic heart failure
J. Thorac. Cardiovasc. Surg., December 1, 2006; 132(6): 1321 - 1328.
[Abstract] [Full Text] [PDF]



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