Published Online
on December 20, 2004

A more recent version of this article appeared on January 4, 2005

This Article Full Text (PDF) Data Supplement All Versions of this Article: 111/1/11    most recent 01.CIR.0000151313.18547.A2v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xue, T. Articles by Li, R. A. Search for Related Content PubMed PubMed Citation Articles by Xue, T. Articles by Li, R. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB LIDOCAINE Related Collections Electrophysiology Pacemaker Arrythmias-basic studies Developmental biology Ion channels/membrane transport Gene therapy Related Article

Submitted on August 19, 2004
Revised on September 23, 2004
Accepted on September 30, 2004

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

Tian Xue PhD, Hee Cheol Cho PhD, Fadi G. Akar PhD, Suk-Ying Tsang PhD, Steven P. Jones PhD, Eduardo Marbán MD, PhD, Gordon F. Tomaselli MD, and Ronald A. Li PhD^*

From the Department of Medicine, Johns Hopkins University, Baltimore, Md.

^* To whom correspondence should be addressed. E-mail: ronaldli{at}jhmi.edu.

Background--Human embryonic stem cells (hESCs) derived from blastocysts can propagate indefinitely in culture while maintaining pluripotency, including the ability to differentiate into cardiomyocytes (CMs); therefore, hESCs may provide an unlimited source of human CMs for cell-based therapies. Although CMs can be derived from hESCs ex vivo, it remains uncertain whether a functional syncytium can be formed between donor and recipient cells after engraftment.

Methods and Results--Using a combination of electrophysiological and imaging techniques, here we demonstrate that electrically active, donor CMs derived from hESCs that had been stably genetically engineered by a recombinant lentivirus can functionally integrate with otherwise-quiescent, recipient, ventricular CMs to induce rhythmic electrical and contractile activities in vitro. The integrated syncytium was responsive to the -adrenergic agonist isoproterenol as well as to other pharmacological agents such as lidocaine and ZD7288. Similarly, a functional hESC-derived pacemaker could be implanted in the left ventricle in vivo. Detailed optical mapping of the epicardial surface of guinea pig hearts transplanted with hESC-derived CMs confirmed the successful spread of membrane depolarization from the site of injection to the surrounding myocardium.

Conclusions--We conclude that electrically active, hESC-derived CMs are capable of actively pacing quiescent, recipient, ventricular CMs in vitro and ventricular myocardium in vivo. Our results may lead to an alternative or a supplemental method for correcting defects in cardiac impulse generation, such as cell-based pacemakers.

Key words: stem cells • cardiac development • viruses • gene therapy • pacemakers

Related Article:

Issue Highlights
Circulation 2005 111: 1. [Extract] [Full Text]

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]

				P. Menasche Stem Cell Therapy for Heart Failure: Are Arrhythmias a Real Safety Concern? Circulation, May 26, 2009; 119(20): 2735 - 2740. [Abstract] [Full Text] [PDF]

				E. Macia and P. A. Boyden Stem Cell Therapy Is Proarrhythmic Circulation, April 7, 2009; 119(13): 1814 - 1823. [Full Text] [PDF]

				X. Zhao, A. Bucchi, R. V. Oren, Y. Kryukova, W. Dun, C. E. Clancy, and R. B. Robinson In vitro characterization of HCN channel kinetics and frequency dependence in myocytes predicts biological pacemaker functionality J. Physiol., April 1, 2009; 587(7): 1513 - 1525. [Abstract] [Full Text] [PDF]

				J. P. Fahrenbach, R. Mejia-Alvarez, and K. Banach The relevance of non-excitable cells for cardiac pacemaker function J. Physiol., December 1, 2007; 585(2): 565 - 578. [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]

				M. Halbach, K. Pfannkuche, F. Pillekamp, A. Ziomka, T. Hannes, M. Reppel, J. Hescheler, and J. Muller-Ehmsen Electrophysiological Maturation and Integration of Murine Fetal Cardiomyocytes After Transplantation Circ. Res., August 31, 2007; 101(5): 484 - 492. [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]

				T. Xue, C.-W. Siu, D. K. Lieu, C.-P. Lau, H.-F. Tse, and R. A. Li Mechanistic Role of If Revealed by Induction of Ventricular Automaticity by Somatic Gene Transfer of Gating-Engineered Pacemaker (HCN) Channels Circulation, April 10, 2007; 115(14): 1839 - 1850. [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]

				D. B. Cowan and F. X. McGowan Jr A Paradigm Shift in Cardiac Pacing Therapy? Circulation, September 5, 2006; 114(10): 986 - 988. [Full Text] [PDF]

				H.-F. Tse, T. Xue, C.-P. Lau, C.-W. Siu, K. Wang, Q.-Y. Zhang, G. F. Tomaselli, F. G. Akar, and R. A. Li Bioartificial Sinus Node Constructed via In Vivo Gene Transfer of an Engineered Pacemaker HCN Channel Reduces the Dependence on Electronic Pacemaker in a Sick-Sinus Syndrome Model Circulation, September 5, 2006; 114(10): 1000 - 1011. [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]

				T. P. de Boer, M. A.G. van der Heyden, M. B. Rook, R. Wilders, R. Broekstra, B. Kok, M. A. Vos, J. M.T. de Bakker, and T. A.B. van Veen Pro-arrhythmogenic potential of immature cardiomyocytes is triggered by low coupling and cluster size Cardiovasc Res, September 1, 2006; 71(4): 704 - 714. [Abstract] [Full Text] [PDF]

				Y.-H. Choi, C. Stamm, P. E. Hammer, K. F. Kwaku, J. J. Marler, I. Friehs, M. Jones, C. M. Rader, N. Roy, M.-T. Eddy, et al. Cardiac Conduction through Engineered Tissue Am. J. Pathol., July 1, 2006; 169(1): 72 - 85. [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]

				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. [Full Text] [PDF]

				R. B. Robinson, M. R. Rosen, P. R. Brink, I. S. Cohen, T. Xue, and R. A. Li Letter Regarding the Article by Xue et al, "Functional Integration of Electrically Active Cardiac Derivatives From Genetically Engineered Human Embryonic Stem Cells With Quiescent Recipient Ventricular Cardiomyocytes" * Response Circulation, August 9, 2005; 112(6): e82 - e83. [Full Text] [PDF]