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Circulation. 2001;103:634-637

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(Circulation. 2001;103:634.)
© 2001 American Heart Association, Inc.


Brief Rapid Communications

Therapeutic Potential of Ex Vivo Expanded Endothelial Progenitor Cells for Myocardial Ischemia

Atsuhiko Kawamoto, MD; Heon-Cheol Gwon, MD; Hideki Iwaguro, MD; Jun-Ichi Yamaguchi, MD; Shigeki Uchida, MD; Haruchika Masuda, MD; Marcy Silver, BS; Hong Ma, BS; Marianne Kearney, BS; Jeffrey M. Isner, MD; Takayuki Asahara, MD

From the Division of Cardiovascular Research, St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass.

Correspondence to Takayuki Asahara, MD, or Jeffrey M. Isner, MD, St Elizabeth’s Medical Center, 736 Cambridge Street, Boston, MA 02135. E-mail VeJeff{at}aol.com

Background—We investigated the therapeutic potential of ex vivo expanded endothelial progenitor cells (EPCs) for myocardial neovascularization.

Methods and Results—Peripheral blood mononuclear cells obtained from healthy human adults were cultured in EPC medium and harvested 7 days later. Myocardial ischemia was induced by ligating the left anterior descending coronary artery in male Hsd:RH-rnu (athymic nude) rats. A total of 106 EPCs labeled with 1,1'-dioctadecyl-1 to 3,3,3',3'-tetramethylindocarbocyanine perchlorate were injected intravenously 3 hours after the induction of myocardial ischemia. Seven days later, fluorescence-conjugated Bandeiraea simplicifolia lectin I was administered intravenously, and the rats were immediately killed. Fluorescence microscopy revealed that transplanted EPCs accumulated in the ischemic area and incorporated into foci of myocardial neovascularization. To determine the impact on left ventricular function, 5 rats (EPC group) were injected intravenously with 106 EPCs 3 hours after ischemia; 5 other rats (control group) received culture media. Echocardiography, performed just before and 28 days after ischemia, disclosed ventricular dimensions that were significantly smaller and fractional shortening that was significantly greater in the EPC group than in the control group by day 28. Regional wall motion was better preserved in the EPC group. After euthanization on day 28, necropsy examination disclosed that capillary density was significantly greater in the EPC group than in the control group. Moreover, the extent of left ventricular scarring was significantly less in rats receiving EPCs than in controls. Immunohistochemistry revealed capillaries that were positive for human-specific endothelial cells.

Conclusions—Ex vivo expanded EPCs incorporate into foci of myocardial neovascularization and have a favorable impact on the preservation of left ventricular function.


Key Words: endothelium • stem cells • ischemia • regeneration • neovascularization




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CirculationHome page
H. Iwasaki, A. Kawamoto, M. Ishikawa, A. Oyamada, S. Nakamori, H. Nishimura, K. Sadamoto, M. Horii, T. Matsumoto, S. Murasawa, et al.
Dose-Dependent Contribution of CD34-Positive Cell Transplantation to Concurrent Vasculogenesis and Cardiomyogenesis for Functional Regenerative Recovery After Myocardial Infarction
Circulation, March 14, 2006; 113(10): 1311 - 1325.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
H. Jin, J. Su, B. Garmy-Susini, J. Kleeman, and J. Varner
Integrin {alpha}4{beta}1 Promotes Monocyte Trafficking and Angiogenesis in Tumors
Cancer Res., February 15, 2006; 66(4): 2146 - 2152.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
N. Werner and G. Nickenig
Influence of Cardiovascular Risk Factors on Endothelial Progenitor Cells: Limitations for Therapy?
Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): 257 - 266.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
Y. Misao, G. Takemura, M. Arai, S. Sato, K. Suzuki, S. Miyata, K.-i. Kosai, S. Minatoguchi, T. Fujiwara, and H. Fujiwara
Bone marrow-derived myocyte-like cells and regulation of repair-related cytokines after bone marrow cell transplantation
Cardiovasc Res, February 1, 2006; 69(2): 476 - 490.
[Abstract] [Full Text] [PDF]


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JEMHome page
G. Qin, M. Ii, M. Silver, A. Wecker, E. Bord, H. Ma, M. Gavin, D. A. Goukassian, Y.-s. Yoon, T. Papayannopoulou, et al.
Functional disruption of {alpha}4 integrin mobilizes bone marrow-derived endothelial progenitors and augments ischemic neovascularization
J. Exp. Med., January 23, 2006; 203(1): 153 - 163.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
J. George, A. Afek, A. Abashidze, H. Shmilovich, V. Deutsch, J. Kopolovich, H. Miller, and G. Keren
Transfer of Endothelial Progenitor and Bone Marrow Cells Influences Atherosclerotic Plaque Size and Composition in Apolipoprotein E Knockout Mice
Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2636 - 2641.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
H. Nakagami, K. Maeda, R. Morishita, S. Iguchi, T. Nishikawa, Y. Takami, Y. Kikuchi, Y. Saito, K. Tamai, T. Ogihara, et al.
Novel Autologous Cell Therapy in Ischemic Limb Disease Through Growth Factor Secretion by Cultured Adipose Tissue-Derived Stromal Cells
Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2542 - 2547.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
D. H. Walter, J. Haendeler, J. Reinhold, U. Rochwalsky, F. Seeger, J. Honold, J. Hoffmann, C. Urbich, R. Lehmann, F. Arenzana-Seisdesdos, et al.
Impaired CXCR4 Signaling Contributes to the Reduced Neovascularization Capacity of Endothelial Progenitor Cells From Patients With Coronary Artery Disease
Circ. Res., November 25, 2005; 97(11): 1142 - 1151.
[Abstract] [Full Text] [PDF]


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CirculationHome page
C. E. Murry, L. J. Field, and P. Menasche
Cell-Based Cardiac Repair: Reflections at the 10-Year Point
Circulation, November 15, 2005; 112(20): 3174 - 3183.
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J CARDIOVASC PHARMACOL THERHome page
R. R. Makkar, M. J. Price, M. Lill, M. Frantzen, K. Takizawa, T. Kleisli, J. Zheng, S. Kar, R. McClelan, T. Miyamota, et al.
Intramyocardial Injection of Allogenic Bone Marrow-Derived Mesenchymal Stem Cells Without Immunosuppression Preserves Cardiac Function in a Porcine Model of Myocardial Infarction
Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2005; 10(4): 225 - 233.
[Abstract] [PDF]


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NEJMHome page
N. Werner, S. Kosiol, T. Schiegl, P. Ahlers, K. Walenta, A. Link, M. Bohm, and G. Nickenig
Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes
N. Engl. J. Med., September 8, 2005; 353(10): 999 - 1007.
[Abstract] [Full Text] [PDF]


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CirculationHome page
C. Kupatt, R. Hinkel, M. Lamparter, M.-L. von Bruhl, T. Pohl, J. Horstkotte, H. Beck, S. Muller, S. Delker, F.-J. Gildehaus, et al.
Retroinfusion of Embryonic Endothelial Progenitor Cells Attenuates Ischemia-Reperfusion Injury in Pigs: Role of Phosphatidylinositol 3-Kinase/AKT Kinase
Circulation, August 30, 2005; 112(9_suppl): I-117 - I-122.
[Abstract] [Full Text] [PDF]


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Eur. J. Cardiothorac. Surg.Home page
M. Siepe, C. Heilmann, P. von Samson, P. Menasche, and F. Beyersdorf
Stem cell research and cell transplantation for myocardial regeneration
Eur. J. Cardiothorac. Surg., August 1, 2005; 28(2): 318 - 324.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
S. Murasawa, A. Kawamoto, M. Horii, S. Nakamori, and T. Asahara
Niche-Dependent Translineage Commitment of Endothelial Progenitor Cells, Not Cell Fusion in General, Into Myocardial Lineage Cells
Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1388 - 1394.
[Abstract] [Full Text] [PDF]


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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.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
N. Nagaya, H. Mori, S. Murakami, K. Kangawa, and S. Kitamura
Adrenomedullin: angiogenesis and gene therapy
Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1432 - R1437.
[Abstract] [Full Text] [PDF]


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CirculationHome page
U. Landmesser, F. Bahlmann, M. Mueller, S. Spiekermann, N. Kirchhoff, S. Schulz, C. Manes, D. Fischer, K. de Groot, D. Fliser, et al.
Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans
Circulation, May 10, 2005; 111(18): 2356 - 2363.
[Abstract] [Full Text] [PDF]


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CirculationHome page
M. A. Costa and D. I. Simon
Molecular Basis of Restenosis and Drug-Eluting Stents
Circulation, May 3, 2005; 111(17): 2257 - 2273.
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Eur. J. Cardiothorac. Surg.Home page
D. Schmidt, A. Mol, S. Neuenschwander, C. Breymann, M. Gossi, G. Zund, M. Turina, and S. P. Hoerstrup
Living patches engineered from human umbilical cord derived fibroblasts and endothelial progenitor cells
Eur. J. Cardiothorac. Surg., May 1, 2005; 27(5): 795 - 800.
[Abstract] [Full Text] [PDF]


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Exp PhysiolHome page
P. Madeddu
Therapeutic angiogenesis and vasculogenesis for tissue regeneration
Exp Physiol, May 1, 2005; 90(3): 315 - 326.
[Abstract] [Full Text] [PDF]


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BloodHome page
D. A. Ingram, L. E. Mead, D. B. Moore, W. Woodard, A. Fenoglio, and M. C. Yoder
Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells
Blood, April 1, 2005; 105(7): 2783 - 2786.
[Abstract] [Full Text] [PDF]


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CirculationHome page
M. Ii, H. Nishimura, A. Iwakura, A. Wecker, E. Eaton, T. Asahara, and D. W. Losordo
Endothelial Progenitor Cells Are Rapidly Recruited to Myocardium and Mediate Protective Effect of Ischemic Preconditioning via "Imported" Nitric Oxide Synthase Activity
Circulation, March 8, 2005; 111(9): 1114 - 1120.
[Abstract] [Full Text] [PDF]


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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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Circ. Res.Home page
K. C. Wollert and H. Drexler
Clinical Applications of Stem Cells for the Heart
Circ. Res., February 4, 2005; 96(2): 151 - 163.
[Abstract] [Full Text] [PDF]


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PhysiologyHome page
S. Murasawa and T. Asahara
Endothelial Progenitor Cells for Vasculogenesis
Physiology, February 1, 2005; 20(1): 36 - 42.
[Abstract] [Full Text] [PDF]


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Nephrol Dial TransplantHome page
M. S. Goligorsky
Whispers and shouts in the pathogenesis of acute renal ischaemia
Nephrol. Dial. Transplant., February 1, 2005; 20(2): 261 - 266.
[Full Text] [PDF]


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Cardiovasc ResHome page
B. Dawn and R. Bolli
Bone marrow cells for cardiac regeneration: the quest for the protagonist continues
Cardiovasc Res, February 1, 2005; 65(2): 293 - 295.
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Cardiovasc ResHome page
S. Davani, F. Deschaseaux, D. Chalmers, P. Tiberghien, and J.-P. Kantelip
Can stem cells mend a broken heart?
Cardiovasc Res, February 1, 2005; 65(2): 305 - 316.
[Abstract] [Full Text] [PDF]


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BloodHome page
O. M. Tepper, J. M. Capla, R. D. Galiano, D. J. Ceradini, M. J. Callaghan, M. E. Kleinman, and G. C. Gurtner
Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells
Blood, February 1, 2005; 105(3): 1068 - 1077.
[Abstract] [Full Text] [PDF]


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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.
[Abstract] [Full Text] [PDF]


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IOVSHome page
N. Sengupta, S. Caballero, R. N. Mames, A. M. Timmers, D. Saban, and M. B. Grant
Preventing Stem Cell Incorporation into Choroidal Neovascularization by Targeting Homing and Attachment Factors
Invest. Ophthalmol. Vis. Sci., January 1, 2005; 46(1): 343 - 348.
[Abstract] [Full Text] [PDF]


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StrokeHome page
U. Ghani, A. Shuaib, A. Salam, A. Nasir, U. Shuaib, T. Jeerakathil, F. Sher, F. O'Rourke, A. M. Nasser, B. Schwindt, et al.
Endothelial Progenitor Cells During Cerebrovascular Disease
Stroke, January 1, 2005; 36(1): 151 - 153.
[Abstract] [Full Text] [PDF]


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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.
[Full Text] [PDF]


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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.
[Abstract] [Full Text] [PDF]