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Circulation. 2003;107:1024-1032
Published online before print February 3, 2003, doi: 10.1161/01.CIR.0000051460.85800.BB
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(Circulation. 2003;107:1024.)
© 2003 American Heart Association, Inc.


Basic Science Reports

Transdifferentiation of Blood-Derived Human Adult Endothelial Progenitor Cells Into Functionally Active Cardiomyocytes

Cornel Badorff, MD; Ralf P. Brandes, MD; Rüdiger Popp, PhD; Stefan Rupp, MD; Carmen Urbich, PhD; Alexandra Aicher, MD; Ingrid Fleming, MD; Rudi Busse, PhD; Andreas M. Zeiher, MD; Stefanie Dimmeler, PhD

From Molecular Cardiology, Department of Internal Medicine IV (C.B., S.R., C.U., A.A., A.M.Z., S.D.), and the Institute for Cardiovascular Physiology (R.P.B., R.P., I.F., R.B), University of Frankfurt, Frankfurt, Germany.

Correspondence to Stefanie Dimmeler, Department of Molecular Cardiology, University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. E-mail dimmeler{at}em.uni-frankfurt.de

Background— Further to promoting angiogenesis, cell therapy may be an approach for cardiac regeneration. Recent studies suggest that progenitor cells can transdifferentiate into other lineages. However, the transdifferentiation potential of endothelial progenitor cells (EPCs) is unknown.

Methods and Results— EPCs were obtained from peripheral blood mononuclear cells of healthy adults or coronary artery disease (CAD) patients by cultivating with endothelial cell medium and growth factors. After 3 days, >95% of adherent cells were functionally and phenotypically EPCs. Diacetylated LDL–labeled EPCs were then cocultivated with rat cardiomyocytes for 6 days, resulting in significant increases of EPC cell length and size to a cardiomyocyte-like morphology. Biochemically, 9.94±1.39% and 5.04±1.09% of EPCs from healthy adults (n=15) or CAD patients (n=14, P<0.01 versus healthy adults), respectively, expressed {alpha}-sarcomeric actinin as measured by flow cytometry. Immunocytochemistry showed that human EPCs expressed {alpha}-sarcomeric actinin, cardiac troponin I (both with partial sarcomeric organization), atrial natriuretic peptide, and myocyte enhancer factor 2. Fluo 4 imaging demonstrated calcium transients synchronized with adjacent rat cardiomyocytes in transdifferentiated human EPCs. Single-cell microinjection of Lucifer yellow and calcein-AM labeling of cardiomyocytes demonstrated gap junctional communication between 51±7% of EPCs (16 hours after labeling, n=4) and cardiomyocytes. EPC transdifferentiation into cardiomyocytes was not observed with conditioned medium but in coculture with paraformaldehyde-fixed cardiomyocytes.

Conclusions— EPCs from healthy volunteers and CAD patients can transdifferentiate in vitro into functionally active cardiomyocytes when cocultivated with rat cardiomyocytes. Cell-to-cell contact but not cellular fusion mediates EPC transdifferentiation. The therapeutic use of autologous EPCs may aid cardiomyocyte regeneration in patients with ischemic heart disease.


Key Words: myocytes • physiology • cells • endothelium




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J Am Coll CardiolHome page
V. Schachinger, B. Assmus, M. B. Britten, J. Honold, R. Lehmann, C. Teupe, N. D. Abolmaali, T. J. Vogl, W.-K. Hofmann, H. Martin, et al.
Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: Final one-year results of the TOPCARE-AMI Trial
J. Am. Coll. Cardiol., October 19, 2004; 44(8): 1690 - 1699.
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CirculationHome page
E. C. Perin, H. F.R. Dohmann, R. Borojevic, S. A. Silva, A. L.S. Sousa, G. V. Silva, C. T. Mesquita, L. Belem, W. K. Vaughn, F. O.D. Rangel, et al.
Improved Exercise Capacity and Ischemia 6 and 12 Months After Transendocardial Injection of Autologous Bone Marrow Mononuclear Cells for Ischemic Cardiomyopathy
Circulation, September 14, 2004; 110(11_suppl_1): II-213 - II-218.
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DevelopmentHome page
M. Bani-Yaghoub, S. E. Kendall, D. P. Moore, S. Bellum, R. A. Cowling, G. N. Nikopoulos, C. J. Kubu, C. Vary, and J. M. Verdi
Insulin acts as a myogenic differentiation signal for neural stem cells with multilineage differentiation potential
Development, September 1, 2004; 131(17): 4287 - 4298.
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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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Am. J. Physiol. Heart Circ. Physiol.Home page
X. Wu, E. Rabkin-Aikawa, K. J. Guleserian, T. E. Perry, Y. Masuda, F. W. H. Sutherland, F. J. Schoen, J. E. Mayer Jr., and J. Bischoff
Tissue-engineered microvessels on three-dimensional biodegradable scaffolds using human endothelial progenitor cells
Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H480 - H487.
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ANN INTERN MEDHome page
M. S. Lee and R. R. Makkar
Stem-Cell Transplantation in Myocardial Infarction: A Status Report
Ann Intern Med, May 4, 2004; 140(9): 729 - 737.
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CirculationHome page
C. Heeschen, R. Lehmann, J. Honold, B. Assmus, A. Aicher, D. H. Walter, H. Martin, A. M. Zeiher, and S. Dimmeler
Profoundly Reduced Neovascularization Capacity of Bone Marrow Mononuclear Cells Derived From Patients With Chronic Ischemic Heart Disease
Circulation, April 6, 2004; 109(13): 1615 - 1622.
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HypertensionHome page
D. E. Stec
Smart Gene Therapy for the Heart
Hypertension, April 1, 2004; 43(4): 720 - 721.
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CirculationHome page
C.-H. Wang, N. Ciliberti, S.-H. Li, P. E. Szmitko, R. D. Weisel, P. W.M. Fedak, M. Al-Omran, W.-J. Cherng, R.-K. Li, W. L. Stanford, et al.
Rosiglitazone Facilitates Angiogenic Progenitor Cell Differentiation Toward Endothelial Lineage: A New Paradigm in Glitazone Pleiotropy
Circulation, March 23, 2004; 109(11): 1392 - 1400.
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Circ. Res.Home page
M. Xaymardan, L. Tang, L. Zagreda, B. Pallante, J. Zheng, J. L. Chazen, A. Chin, I. Duignan, P. Nahirney, S. Rafii, et al.
Platelet-Derived Growth Factor-AB Promotes the Generation of Adult Bone Marrow-Derived Cardiac Myocytes
Circ. Res., March 19, 2004; 94(5): e39 - e45.
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JEMHome page
M. Xaymardan, J. Zheng, I. Duignan, A. Chin, J. M. Holm, V. L.T. Ballard, and J. M. Edelberg
Senescent Impairment in Synergistic Cytokine Pathways That Provide Rapid Cardioprotection in the Rat Heart
J. Exp. Med., March 15, 2004; 199(6): 797 - 804.
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J. Clin. Pathol.Home page
M R Alison, R Poulsom, W R Otto, P Vig, M Brittan, N C Direkze, M Lovell, T C Fang, S L Preston, and N A Wright
Recipes for adult stem cell plasticity: fusion cuisine or readymade?
J. Clin. Pathol., February 1, 2004; 57(2): 113 - 120.
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Cardiovasc ResHome page
D. Skowasch, A. Jabs, R. Andrie, S. Dinkelbach, B. Luderitz, and G. Bauriedel
Presence of bone-marrow- and neural-crest-derived cells in intimal hyperplasia at the time of clinical in-stent restenosis
Cardiovasc Res, December 1, 2003; 60(3): 684 - 691.
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Circ. Res.Home page
R. Gulati, D. Jevremovic, T. E. Peterson, S. Chatterjee, V. Shah, R. G. Vile, and R. D. Simari
Diverse Origin and Function of Cells With Endothelial Phenotype Obtained From Adult Human Blood
Circ. Res., November 28, 2003; 93(11): 1023 - 1025.
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CirculationHome page
M.B. Britten, N.D. Abolmaali, B. Assmus, R. Lehmann, J. Honold, J. Schmitt, T.J. Vogl, H. Martin, V. Schachinger, S. Dimmeler, et al.
Infarct Remodeling After Intracoronary Progenitor Cell Treatment in Patients With Acute Myocardial Infarction (TOPCARE-AMI): Mechanistic Insights From Serial Contrast-Enhanced Magnetic Resonance Imaging
Circulation, November 4, 2003; 108(18): 2212 - 2218.
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CirculationHome page
E. T.H. Yeh, S. Zhang, H. D. Wu, M. Korbling, J. T. Willerson, and Z. Estrov
Transdifferentiation of Human Peripheral Blood CD34+-Enriched Cell Population Into Cardiomyocytes, Endothelial Cells, and Smooth Muscle Cells In Vivo
Circulation, October 28, 2003; 108(17): 2070 - 2073.
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Proc. Natl. Acad. Sci. USAHome page
H. Oh, S. B. Bradfute, T. D. Gallardo, T. Nakamura, V. Gaussin, Y. Mishina, J. Pocius, L. H. Michael, R. R. Behringer, D. J. Garry, et al.
Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction
PNAS, October 14, 2003; 100(21): 12313 - 12318.
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M. Pesce, A. Orlandi, M. G. Iachininoto, S. Straino, A. R. Torella, V. Rizzuti, G. Pompilio, G. Bonanno, G. Scambia, and M. C. Capogrossi
Myoendothelial Differentiation of Human Umbilical Cord Blood-Derived Stem Cells in Ischemic Limb Tissues
Circ. Res., September 5, 2003; 93 (5): e51 - e62.
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Genes Dev.Home page
E. N. Olson and M. D. Schneider
Sizing up the heart: development redux in disease
Genes & Dev., August 15, 2003; 17(16): 1937 - 1956.
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CirculationHome page
P. E. Szmitko, P. W.M. Fedak, R. D. Weisel, D. J. Stewart, M. J.B. Kutryk, and S. Verma
Endothelial Progenitor Cells: New Hope for a Broken Heart
Circulation, June 24, 2003; 107(24): 3093 - 3100.
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CirculationHome page
E. C. Perin, H. F.R. Dohmann, R. Borojevic, S. A. Silva, A. L.S. Sousa, C. T. Mesquita, M. I.D. Rossi, A. C. Carvalho, H. S. Dutra, H. J.F. Dohmann, et al.
Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure
Circulation, May 13, 2003; 107(18): 2294 - 2302.
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P. Anversa, J. Kajstura, B. Nadal-Ginard, and A. Leri
Primitive Cells and Tissue Regeneration
Circ. Res., April 4, 2003; 92(6): 579 - 582.
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