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.
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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 |
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