Circulation. 2003;107:2733-2740
Published online before print May 12, 2003, doi: 10.1161/01.CIR.0000068356.38592.68
Published online before print May 12, 2003, doi: 10.1161/01.CIR.0000068356.38592.68
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;107:2733.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Differentiation of Human Embryonic Stem Cells to Cardiomyocytes
Role of Coculture With Visceral Endoderm-Like Cells
From the Hubrecht Laboratory (C.M., D.W.v.O., R.S., S.v.d.B., R.H., R.P., L.T.); the Departments of Medical Physiology (M.v.d.H., T.O.), Cardiothoracic Surgery (R.H., A.B.d.l.R.), and Cardiology (P.D.), University Medical Center Utrecht; and the Interuniversity Cardiology Institute of the Netherlands (C.M., P.D., R.P.), Utrecht, Netherlands; and the Monash Institute of Reproduction and Development, Melbourne Australia (M.P.).
Correspondence to Christine Mummery, Hubrecht Laboratory, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands. E-mail christin{at}niob.knaw.nl
Background— Cardiomyocytes derived from human embryonic stem (hES) cells could be useful in restoring heart function after myocardial infarction or in heart failure. Here, we induced cardiomyocyte differentiation of hES cells by a novel method and compared their electrophysiological properties and coupling with those of primary human fetal cardiomyocytes.
Methods and Results— hES cells were cocultured with visceral-endoderm (VE)–like cells from the mouse. This initiated differentiation to beating muscle. Sarcomeric marker proteins, chronotropic responses, and ion channel expression and function were typical of cardiomyocytes. Electrophysiology demonstrated that most cells resembled human fetal ventricular cells. Real-time intracellular calcium measurements, Lucifer yellow injection, and connexin 43 expression demonstrated that fetal and hES-derived cardiomyocytes are coupled by gap junctions in culture. Inhibition of electrical responses by verapamil demonstrated the presence of functional 
1c-calcium ion channels.
Conclusions— This is the first demonstration of induction of cardiomyocyte differentiation in hES cells that do not undergo spontaneous cardiogenesis. It provides a model for the study of human cardiomyocytes in culture and could be a step forward in the development of cardiomyocyte transplantation therapies.
Key Words: electrophysiology • myocytes • stem cells
Related Article:
Circulation 2003 107: 2638-2639.
This article has been cited by other articles:
 |
|
 |
|
  J. Liu, D. K. Lieu, C. W. Siu, J.-D. Fu, H.-F. Tse, and R. A. Li Facilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression Am J Physiol Cell Physiol, July 1, 2009; 297(1): C152 - C159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Takei, H. Ichikawa, K. Johkura, A. Mogi, H. No, S. Yoshie, D. Tomotsune, and K. Sasaki Bone morphogenetic protein-4 promotes induction of cardiomyocytes from human embryonic stem cells in serum-based embryoid body development Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1793 - H1803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Seewald, P. Ellinghaus, A. Kassner, I. Stork, M. Barg, S. Niebrugge, S. Golz, H. Summer, R. Zweigerdt, E.-M. Schrader, et al. Genomic profiling of developing cardiomyocytes from recombinant murine embryonic stem cells reveals regulation of transcription factor clusters Physiol Genomics, June 1, 2009; 38(1): 7 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhang, G. F. Wilson, A. G. Soerens, C. H. Koonce, J. Yu, S. P. Palecek, J. A. Thomson, and T. J. Kamp Functional Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells Circ. Res., February 27, 2009; 104(4): e30 - e41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Mauritz, K. Schwanke, M. Reppel, S. Neef, K. Katsirntaki, L. S. Maier, F. Nguemo, S. Menke, M. Haustein, J. Hescheler, et al. Generation of Functional Murine Cardiac Myocytes From Induced Pluripotent Stem Cells Circulation, July 29, 2008; 118(5): 507 - 517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Synnergren, K. Akesson, K. Dahlenborg, H. Vidarsson, C. Ameen, D. Steel, A. Lindahl, B. Olsson, and P. Sartipy Molecular Signature of Cardiomyocyte Clusters Derived from Human Embryonic Stem Cells Stem Cells, July 1, 2008; 26(7): 1831 - 1840. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Nelson, R. S. Faustino, A. Chiriac, R. Crespo-Diaz, A. Behfar, and A. Terzic CXCR4+/FLK-1+ Biomarkers Select a Cardiopoietic Lineage from Embryonic Stem Cells Stem Cells, June 1, 2008; 26(6): 1464 - 1473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Freund, D. Ward-van Oostwaard, J. Monshouwer-Kloots, S. van den Brink, M. van Rooijen, X. Xu, R. Zweigerdt, C. Mummery, and R. Passier Insulin Redirects Differentiation from Cardiogenic Mesoderm and Endoderm to Neuroectoderm in Differentiating Human Embryonic Stem Cells Stem Cells, March 1, 2008; 26(3): 724 - 733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Arrell, N. J. Niederlander, R. S. Faustino, A. Behfar, and A. Terzic Cardioinductive Network Guiding Stem Cell Differentiation Revealed by Proteomic Cartography of Tumor Necrosis Factor {alpha}-Primed Endodermal Secretome Stem Cells, February 1, 2008; 26(2): 387 - 400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Raya, I. Rodriguez-Piza, B. Aran, A. Consiglio, P.N. Barri, A. Veiga, and J.C. I. Belmonte Generation of Cardiomyocytes from New Human Embryonic Stem Cell Lines Derived from Poor-quality Blastocysts Cold Spring Harb Symp Quant Biol, January 1, 2008; 73(0): 127 - 135. [Abstract] [PDF]
|
|
|
|
|
|
J. Liu, J. D. Fu, C. W. Siu, and R. A. Li Functional Sarcoplasmic Reticulum for Calcium Handling of Human Embryonic Stem Cell-Derived Cardiomyocytes: Insights for Driven Maturation Stem Cells, December 1, 2007; 25(12): 3038 - 3044. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Caspi, I. Huber, I. Kehat, M. Habib, G. Arbel, A. Gepstein, L. Yankelson, D. Aronson, R. Beyar, and L. Gepstein Transplantation of Human Embryonic Stem Cell-Derived Cardiomyocytes Improves Myocardial Performance in Infarcted Rat Hearts J. Am. Coll. Cardiol., November 6, 2007; 50(19): 1884 - 1893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Janssens Human embryonic stem cells for cardiac repair: the focus is on refined selection and cardiopoietic programming Heart, October 1, 2007; 93(10): 1173 - 1174. [Full Text] [PDF]
|
|
|
|
|
|
J. Leor, S. Gerecht, S. Cohen, L. Miller, R. Holbova, A. Ziskind, M. Shachar, M. S Feinberg, E. Guetta, and J. Itskovitz-Eldor Human embryonic stem cell transplantation to repair the infarcted myocardium Heart, October 1, 2007; 93(10): 1278 - 1284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Batten, N. A Rosenthal, and M. H Yacoub Immune response to stem cells and strategies to induce tolerance Phil Trans R Soc B, August 29, 2007; 362(1484): 1343 - 1356. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Huber, I. Itzhaki, O. Caspi, G. Arbel, M. Tzukerman, A. Gepstein, M. Habib, L. Yankelson, I. Kehat, and L. Gepstein Identification and selection of cardiomyocytes during human embryonic stem cell differentiation FASEB J, August 1, 2007; 21(10): 2551 - 2563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Baharvand, A. Fathi, D. van Hoof, and G. H. Salekdeh Concise Review: Trends in Stem Cell Proteomics Stem Cells, August 1, 2007; 25(8): 1888 - 1903. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Denham, B. J. Conley, F. Olsson, L. Gulluyan, T. J. Cole, and R. Mollard A murine respiratory-inducing niche displays variable efficiency across human and mouse embryonic stem cell species Am J Physiol Lung Cell Mol Physiol, May 1, 2007; 292(5): L1241 - L1247. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Sartiani, E. Bettiol, F. Stillitano, A. Mugelli, E. Cerbai, and M. E. Jaconi Developmental Changes in Cardiomyocytes Differentiated from Human Embryonic Stem Cells: A Molecular and Electrophysiological Approach Stem Cells, May 1, 2007; 25(5): 1136 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. Burridge, D. Anderson, H. Priddle, M. D. Barbadillo Munoz, S. Chamberlain, C. Allegrucci, L. E. Young, and C. Denning Improved Human Embryonic Stem Cell Embryoid Body Homogeneity and Cardiomyocyte Differentiation from a Novel V-96 Plate Aggregation System Highlights Interline Variability Stem Cells, April 1, 2007; 25(4): 929 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Behfar, C. Perez-Terzic, R. S. Faustino, D. K. Arrell, D. M. Hodgson, S. Yamada, M. Puceat, N. Niederlander, A. E Alekseev, L. V. Zingman, et al. Cardiopoietic programming of embryonic stem cells for tumor-free heart repair J. Exp. Med., February 19, 2007; 204(2): 405 - 420. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. W. van Laake, R. Hassink, P. A. Doevendans, and C. Mummery Heart repair and stem cells J. Physiol., December 1, 2006; 577(2): 467 - 478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Caspi and L. Gepstein Stem cells for myocardial repair Eur. Heart J. Suppl., September 1, 2006; 8(suppl_E): E43 - E54. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Beqqali, J. Kloots, D. Ward-van Oostwaard, C. Mummery, and R. Passier Genome-Wide Transcriptional Profiling of Human Embryonic Stem Cells Differentiating to Cardiomyocytes Stem Cells, August 1, 2006; 24(8): 1956 - 1967. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-H. Zimmermann, M. Didie, S. Doker, I. Melnychenko, H. Naito, C. Rogge, M. Tiburcy, and T. Eschenhagen Heart muscle engineering: An update on cardiac muscle replacement therapy Cardiovasc Res, August 1, 2006; 71(3): 419 - 429. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A.G. van der Heyden, T. J.M. Wijnhoven, and T. Opthof Molecular aspects of adrenergic modulation of the transient outward current Cardiovasc Res, August 1, 2006; 71(3): 430 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Van Hoof, R. Passier, D. Ward-Van Oostwaard, M. W. H. Pinkse, A. J. R. Heck, C. L. Mummery, and J. Krijgsveld A Quest for Human and Mouse Embryonic Stem Cell-specific Proteins Mol. Cell. Proteomics, July 1, 2006; 5(7): 1261 - 1273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Schwanke, S. Wunderlich, M. Reppel, M. E. Winkler, M. Matzkies, S. Groos, J. Itskovitz-Eldor, A. R. Simon, J. Hescheler, A. Haverich, et al. Generation and Characterization of Functional Cardiomyocytes from Rhesus Monkey Embryonic Stem Cells Stem Cells, June 1, 2006; 24(6): 1423 - 1432. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Trounson The Production and Directed Differentiation of Human Embryonic Stem Cells Endocr. Rev., April 1, 2006; 27(2): 208 - 219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Priddle, D. R. E. Jones, P. W. Burridge, and R. Patient Hematopoiesis from Human Embryonic Stem Cells: Overcoming the Immune Barrier in Stem Cell Therapies Stem Cells, April 1, 2006; 24(4): 815 - 824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Eschenhagen, W. H. Zimmermann, and A. G. Kleber Electrical Coupling of Cardiac Myocyte Cell Sheets to the Heart Circ. Res., March 17, 2006; 98(5): 573 - 575. [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Raikwar, T. Mueller, and N. Zavazava Strategies for Developing Therapeutic Application of Human Embryonic Stem Cells Physiology, February 1, 2006; 21(1): 19 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Dolnikov, M. Shilkrut, N. Zeevi-Levin, S. Gerecht-Nir, M. Amit, A. Danon, J. Itskovitz-Eldor, and O. Binah Functional Properties of Human Embryonic Stem Cell-Derived Cardiomyocytes: Intracellular Ca2+ Handling and the Role of Sarcoplasmic Reticulum in the Contraction Stem Cells, February 1, 2006; 24(2): 236 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Drukker, H. Katchman, G. Katz, S. Even-Tov Friedman, E. Shezen, E. Hornstein, O. Mandelboim, Y. Reisner, and N. Benvenisty Human Embryonic Stem Cells and Their Differentiated Derivatives Are Less Susceptible to Immune Rejection Than Adult Cells Stem Cells, February 1, 2006; 24(2): 221 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Eschenhagen and W. H. Zimmermann Engineering Myocardial Tissue Circ. Res., December 9, 2005; 97(12): 1220 - 1231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Wang, T. Xue, S.-Y. Tsang, R. Van Huizen, C. W. Wong, K. W. Lai, Z. Ye, L. Cheng, K. W. Au, J. Zhang, et al. Electrophysiological Properties of Pluripotent Human and Mouse Embryonic Stem Cells Stem Cells, October 1, 2005; 23(10): 1526 - 1534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Brodie and H. D. Humes Stem Cell Approaches for the Treatment of Renal Failure Pharmacol. Rev., September 1, 2005; 57(3): 299 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Laflamme, J. Gold, C. Xu, M. Hassanipour, E. Rosler, S. Police, V. Muskheli, and C. E. Murry Formation of Human Myocardium in the Rat Heart from Human Embryonic Stem Cells Am. J. Pathol., September 1, 2005; 167(3): 663 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.-J. Swijnenburg, M. Tanaka, H. Vogel, J. Baker, T. Kofidis, F. Gunawan, D. R. Lebl, A. D. Caffarelli, J. L. de Bruin, E. V. Fedoseyeva, et al. Embryonic Stem Cell Immunogenicity Increases Upon Differentiation After Transplantation Into Ischemic Myocardium Circulation, August 30, 2005; 112(9_suppl): I-166 - I-172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Dudley Jr Beware of Cells Bearing Gifts: Cell Replacement Therapy and Arrhythmic Risk Circ. Res., July 22, 2005; 97(2): 99 - 101. [Full Text] [PDF]
|
|
|
|
|
|
R. Passier, D. W.-v. Oostwaard, J. Snapper, J. Kloots, R. J. Hassink, E. Kuijk, B. Roelen, A. B. de la Riviere, and C. Mummery Increased Cardiomyocyte Differentiation from Human Embryonic Stem Cells in Serum-Free Cultures Stem Cells, June 1, 2005; 23(6): 772 - 780. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Lagostena, D. Avitabile, E. De Falco, A. Orlandi, F. Grassi, M. G. Iachininoto, G. Ragone, S. Fucile, G. Pompilio, F. Eusebi, et al. Electrophysiological properties of mouse bone marrow c-kit+ cells co-cultured onto neonatal cardiac myocytes Cardiovasc Res, June 1, 2005; 66(3): 482 - 492. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Keller Embryonic stem cell differentiation: emergence of a new era in biology and medicine Genes & Dev., May 15, 2005; 19(10): 1129 - 1155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Wobus and K. R. Boheler Embryonic Stem Cells: Prospects for Developmental Biology and Cell Therapy Physiol Rev, April 1, 2005; 85(2): 635 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Foley and M. Mercola Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex Genes & Dev., February 1, 2005; 19(3): 387 - 396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Xue, H. C. Cho, F. G. Akar, S.-Y. Tsang, S. P. Jones, E. Marban, G. F. Tomaselli, and R. A. Li Functional Integration of Electrically Active Cardiac Derivatives From Genetically Engineered Human Embryonic Stem Cells With Quiescent Recipient Ventricular Cardiomyocytes: Insights Into the Development of Cell-Based Pacemakers Circulation, January 4, 2005; 111(1): 11 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A.G. van der Heyden, T. J.M. Wijnhoven, and T. Opthof Molecular aspects of adrenergic modulation of cardiac L-type Ca2+ channels Cardiovasc Res, January 1, 2005; 65(1): 28 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Pera and A. O. Trounson Human embryonic stem cells: prospects for development Development, November 15, 2004; 131(22): 5515 - 5525. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Stojkovic, M. Lako, T. Strachan, and A. Murdoch Derivation, growth and applications of human embryonic stem cells Reproduction, September 1, 2004; 128(3): 259 - 267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Satin, I. Kehat, O. Caspi, I. Huber, G. Arbel, I. Itzhaki, J. Magyar, E. A. Schroder, I. Perlman, and L. Gepstein Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes J. Physiol., September 1, 2004; 559(2): 479 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Rudy-Reil and J. Lough Avian Precardiac Endoderm/Mesoderm Induces Cardiac Myocyte Differentiation in Murine Embryonic Stem Cells Circ. Res., June 25, 2004; 94(12): e107 - e116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Trounson Stem cells, plasticity and cancer - uncomfortable bed fellows Development, June 15, 2004; 131(12): 2763 - 2768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gepstein, Y. Feld, and L. Yankelson Somatic gene and cell therapy strategies for the treatment of cardiac arrhythmias Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H815 - H822. [Full Text] [PDF]
|
|
|
|
|
|
R. D. Vanderlaan, G. Y. Oudit, and P. H. Backx Electrophysiological Profiling of Cardiomyocytes in Embryonic Bodies Derived From Human Embryonic Stem Cells: Therapeutic Implications Circ. Res., July 11, 2003; 93(1): 1 - 3. [Full Text] [PDF]
|
|
|
|
|
|
T. Nakamura and M. D. Schneider The Way to a Human's Heart Is Through the Stomach: Visceral Endoderm-Like Cells Drive Human Embryonic Stem Cells to a Cardiac Fate Circulation, June 3, 2003; 107(21): 2638 - 2639. [Full Text] [PDF]
|
|