This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: j.jacc.2007.07.054v1 50/19/1884    most recent 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 Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Caspi, O. Articles by Gepstein, L. Search for Related Content PubMed Articles by Caspi, O. Articles by Gepstein, L. Related Collections Related Article

PRECLINICAL STUDY

Transplantation of Human Embryonic Stem Cell-Derived Cardiomyocytes Improves Myocardial Performance in Infarcted Rat Hearts

Oren Caspi, MD^_*, Irit Huber, PhD^_*, Izhak Kehat, MD, PhD^_*,, Manhal Habib, MD^_*, Gil Arbel, MSc^_*, Amira Gepstein, PhD^_*, Lior Yankelson, MD^_*, Doron Aronson, MD,, Rafael Beyar, MD, PhD and Lior Gepstein, MD, PhD^_*,,_*

^_* Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, the Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, Israel
Cardiology Department, Rambam Medical Center, Haifa, Israel

Manuscript received March 5, 2007; revised manuscript received July 26, 2007, accepted July 30, 2007.

^_* Reprint requests and correspondence: Dr. Lior Gepstein, Technion's Faculty of Medicine, P.O. Box 9649, Haifa, 31096, Israel. (Email: mdlior{at}tx.technion.ac.il).

Objectives: We evaluated the ability of human embryonic stem cells (hESCs) and their cardiomyocyte derivatives (hESC-CMs) to engraft and improve myocardial performance in the rat chronic infarction model.

Background: Cell therapy is emerging as a novel therapy for myocardial repair but is hampered by the lack of sources for human cardiomyocytes.

Methods: Immunosuppressed healthy and infarcted (7 to 10 days after coronary ligation) rat hearts were randomized to injection of undifferentiated hESCs, hESC-CMs, noncardiomyocyte hESC derivatives, or saline. Detailed histological analysis and sequential echocardiography were used to determine the structural and functional consequences of cell grafting.

Results: Transplantation of undifferentiated hESCs resulted in the formation of teratoma-like structures. This phenomenon was prevented by grafting of ex vivo pre-differentiated hESC-CMs. The grafted cardiomyocytes survived, proliferated, matured, aligned, and formed gap junctions with host cardiac tissue. Functionally, animals injected with saline or nonmyocyte hESC derivatives demonstrated significant left ventricular (LV) dilatation and functional deterioration, whereas grafting of hESC-CMs attenuated this remodeling process. Hence, post-injury baseline fractional shortening deteriorated by 50% (from 20 ± 2% to 10 ± 2%) and by 30% (20 ± 2% to 14 ± 2%) in the saline and nonmyocyte groups while improving by 22% (21 ± 2% to 25 ± 3%) in the hESC-CM group. Similarly, wall motion score index and LV diastolic dimensions were significantly lower in the hESC-CM animals.

Conclusions: Transplantation of hESC-CMs after extensive myocardial infarction in rats results in the formation of stable cardiomyocyte grafts, attenuation of the remodeling process, and functional benefit. These findings highlight the potential of hESCs for myocardial cell therapy strategies.

Abbreviations and Acronyms   eGFP = enhanced green fluorescent protein   FS = fractional shortening   hESC = human embryonic stem cell   hESC-CM = human embryonic stem cell–derived cardiomyocyte   HLA = human leukocyte antigen   LAD = left anterior descending coronary artery   LV = left ventricle/ventricular   LVDd = left ventricular end-diastolic diameter   MLC-2a = myosin light chain-2a   PCR = polymerase chain reaction   Tn = troponin

Related Article

Human Stem Cells for Heart Failure Treatment: Ready for Prime Time?

Gianluigi Condorelli and Daniele Catalucci
J. Am. Coll. Cardiol. 2007 50: 1894-1895. [Full Text] [PDF]

This article has been cited by other articles:

				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]

				R.-J. Swijnenburg, S. Schrepfer, J. A. Govaert, F. Cao, K. Ransohoff, A. Y. Sheikh, M. Haddad, A. J. Connolly, M. M. Davis, R. C. Robbins, et al. Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts PNAS, September 2, 2008; 105(35): 12991 - 12996. [Abstract] [Full Text] [PDF]

				N. L. Tulloch, L. Pabon, and C. E. Murry Get With the (Re)Program: Cardiovascular Potential of Skin-Derived Induced Pluripotent Stem Cells Circulation, July 29, 2008; 118(5): 472 - 475. [Full Text] [PDF]

				A. N. DeMaria, J. J. Bax, O. Ben-Yehuda, P. Clopton, G. K. Feld, G. S. Ginsburg, B. H. Greenberg, J. D. Knoke, W. Y.W. Lew, J. A.C. Lima, et al. Highlights of the year in JACC 2007. J. Am. Coll. Cardiol., January 29, 2008; 51(4): 490 - 512. [Full Text] [PDF]

				G. Condorelli and D. Catalucci Human Stem Cells for Heart Failure Treatment: Ready for Prime Time? J. Am. Coll. Cardiol., November 6, 2007; 50(19): 1894 - 1895. [Full Text] [PDF]