Circulation Research. 2003;93:32-39
Published online before print June 5, 2003, doi: 10.1161/01.RES.0000080317.92718.99
Published online before print June 5, 2003, doi: 10.1161/01.RES.0000080317.92718.99
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2003 American Heart Association, Inc.
Cellular Biology |
Human Embryonic Stem Cells Develop Into Multiple Types of Cardiac Myocytes
Action Potential Characterization
From the Departments of Anatomy (Y.M., Y.L., J.A.T.), Medicine (T.J.K.), and Physiology (J.Q.H., T.J.K.), National Primate Research Center (Y.M., J.A.T), University of Wisconsin, Madison, Wis.
Correspondence to Dr Timothy J. Kamp, University of Wisconsin-Madison, H6/343 Clinical Science Center, 600 Highland Ave, Madison, WI 53792-3248. E-mail tjk{at}medicine.wisc.edu
Human embryonic stem (hES) cells can differentiate in vitro, forming embryoid bodies (EBs) composed of derivatives of all three embryonic germ layers. Spontaneously contracting outgrowths from these EBs contain cardiomyocytes (CMs); however, the types of human CMs and their functional properties are unknown. This study characterizes the contractions and action potentials (APs) from beating EB outgrowths cultured for 40 to 95 days. Spontaneous and electrical field-stimulated contractions were measured with video edge-detection microscopy. ß-Adrenergic stimulation with 1.0 µmol/L isoproterenol resulted in a significant increase in contraction magnitude. Intracellular electrical recordings using sharp KCl microelectrodes in beating EB outgrowths revealed three distinct classes of APs: nodal-like, embryonic atrial-like, and embryonic ventricular-like. The APs were described as embryonic based on the relatively depolarized resting membrane potential and slow AP upstroke. Repeated impalements of an individual beating outgrowth revealed a reproducible AP morphology recorded from different cells, suggesting that each outgrowth is composed of a predominant cell type. Complex functional properties typical of cardiac muscle were observed in the hES cell-derived CMs including rate adaptation of AP duration and provoked early and delayed afterdepolarizations. Repolarization of the AP showed a significant role for IKr based on E-4031 induced prolongation of AP duration as anticipated for human CMs. In conclusion, hES cells can differentiate into multiple types of CMs displaying functional properties characteristic of embryonic human cardiac muscle. Thus, hES provide a renewable source of distinct types of human cardiac myocytes for basic research, pharmacological testing, and potentially therapeutic applications.
Key Words: human embryonic stem cells • action potential • cellular electrophysiology • pharmacology • cardiomyocytes
This article has been cited by other articles:
 |
|
 |
|
  V. Valiunas, G. Kanaporis, L. Valiuniene, C. Gordon, H. Z. Wang, L. Li, R. B. Robinson, M. R. Rosen, I. S. Cohen, and P. R. Brink Coupling an HCN2-expressing cell to a myocyte creates a two-cell pacing unit J. Physiol., November 1, 2009; 587(21): 5211 - 5226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Kaufman Toward clinical therapies using hematopoietic cells derived from human pluripotent stem cells Blood, October 22, 2009; 114(17): 3513 - 3523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zwi, O. Caspi, G. Arbel, I. Huber, A. Gepstein, I.-H. Park, and L. Gepstein Cardiomyocyte Differentiation of Human Induced Pluripotent Stem Cells Circulation, October 13, 2009; 120(15): 1513 - 1523. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 W. Habeler, S. Pouillot, A. Plancheron, M. Puceat, M. Peschanski, and C. Monville An in vitro beating heart model for long-term assessment of experimental therapeutics Cardiovasc Res, February 1, 2009; 81(2): 253 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Reinecke, E. Minami, W.-Z. Zhu, and M. A. Laflamme Cardiogenic Differentiation and Transdifferentiation of Progenitor Cells Circ. Res., November 7, 2008; 103(10): 1058 - 1071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Martin, P. S. Woll, Z. Ni, J. C. Zuniga-Pflucker, and D. S. Kaufman Differences in lymphocyte developmental potential between human embryonic stem cell and umbilical cord blood-derived hematopoietic progenitor cells Blood, October 1, 2008; 112(7): 2730 - 2737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Pedrotty, R. Y. Klinger, N. Badie, S. Hinds, A. Kardashian, and N. Bursac Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H390 - H400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Thomas, S. Friedman, and R.-Y. Lin Thyroid stem cells: lessons from normal development and thyroid cancer Endocr. Relat. Cancer, March 1, 2008; 15(1): 51 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Lehnart, M. J. Ackerman, D. W. Benson Jr, R. Brugada, C. E. Clancy, J. K. Donahue, A. L. George Jr, A. O. Grant, S. C. Groft, C. T. January, et al. Inherited Arrhythmias: A National Heart, Lung, and Blood Institute and Office of Rare Diseases Workshop Consensus Report About the Diagnosis, Phenotyping, Molecular Mechanisms, and Therapeutic Approaches for Primary Cardiomyopathies of Gene Mutations Affecting Ion Channel Function Circulation, November 13, 2007; 116(20): 2325 - 2345. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
N. Kapur and K. Banach Inositol-1,4,5-trisphosphate-mediated spontaneous activity in mouse embryonic stem cell-derived cardiomyocytes J. Physiol., June 15, 2007; 581(3): 1113 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Guan, S. Wagner, B. Unsold, L. S. Maier, D. Kaiser, B. Hemmerlein, K. Nayernia, W. Engel, and G. Hasenfuss Generation of Functional Cardiomyocytes From Adult Mouse Spermatogonial Stem Cells Circ. Res., June 8, 2007; 100(11): 1615 - 1625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Chen, R. M. Wilson, H. Kubo, R. M. Berretta, D. M. Harris, X. Zhang, N. Jaleel, S. M. MacDonnell, C. Bearzi, J. Tillmanns, et al. Adolescent Feline Heart Contains a Population of Small, Proliferative Ventricular Myocytes With Immature Physiological Properties Circ. Res., March 2, 2007; 100(4): 536 - 544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kurata, H. Matsuda, I. Hisatome, and T. Shibamoto Effects of pacemaker currents on creation and modulation of human ventricular pacemaker: theoretical study with application to biological pacemaker engineering Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H701 - H718. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Norstrom, K. Akesson, T. Hardarson, L. Hamberger, P. Bjorquist, and P. Sartipy Molecular and Pharmacological Properties of Human Embryonic Stem Cell-Derived Cardiomyocytes Experimental Biology and Medicine, December 1, 2006; 231(11): 1753 - 1762. [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]
|
|
|
|
|
|
X.-M. Guo, Y.-S. Zhao, H.-X. Chang, C.-Y. Wang, L.-L. E, X.-A. Zhang, C.-M. Duan, L.-Z. Dong, H. Jiang, J. Li, et al. Creation of Engineered Cardiac Tissue In Vitro From Mouse Embryonic Stem Cells Circulation, May 9, 2006; 113(18): 2229 - 2237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Murry, H. Reinecke, and L. M. Pabon Regeneration Gaps: Observations on Stem Cells and Cardiac Repair J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1777 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yao, S. Chen, J. Clark, E. Hao, G. M. Beattie, A. Hayek, and S. Ding Long-term self-renewal and directed differentiation of human embryonic stem cells in chemically defined conditions PNAS, May 2, 2006; 103(18): 6907 - 6912. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. W. Chaudhary, N. X. Barrezueta, M. B. Bauchmann, A. J. Milici, G. Beckius, D. B. Stedman, J. E. Hambor, W. L. Blake, J. D. McNeish, A. Bahinski, et al. Embryonic Stem Cells in Predictive Cardiotoxicity: Laser Capture Microscopy Enables Assay Development Toxicol. Sci., March 1, 2006; 90(1): 149 - 158. [Abstract] [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]
|
|
|
|
 |
|
 M. T. Kuhlmann, P. Kirchhof, R. Klocke, L. Hasib, J. Stypmann, L. Fabritz, M. Stelljes, W. Tian, M. Zwiener, M. Mueller, et al. G-CSF/SCF reduces inducible arrhythmias in the infarcted heart potentially via increased connexin43 expression and arteriogenesis J. Exp. Med., January 23, 2006; 203(1): 87 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Leri, J. Kajstura, and P. Anversa Cardiac Stem Cells and Mechanisms of Myocardial Regeneration Physiol Rev, October 1, 2005; 85(4): 1373 - 1416. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C Chachques, C. Salanson-Lajos, P. Lajos, A. Shafy, A. Alshamry, and A. Carpentier Cellular Cardiomyoplasty for Myocardial Regeneration Asian Cardiovasc Thorac Ann, September 1, 2005; 13(3): 287 - 296. [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]
|
|
|
|
|
|
M. Rubart and D. P. Zipes Genes and Cardiac Repolarization: The Challenge Ahead Circulation, August 30, 2005; 112(9): 1242 - 1244. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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. 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]
|
|
|
|
|
|
D. M. Hodgson, A. Behfar, L. V. Zingman, G. C. Kane, C. Perez-Terzic, A. E. Alekseev, M. Puceat, and A. Terzic Stable benefit of embryonic stem cell therapy in myocardial infarction Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H471 - H479. [Abstract] [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]
|
|