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a The Bruce Rappaport Institute in the Medical Sciences, Faculty of Medicine, Technion, Israel Institute of Technology, and the Cardiology Department, Rambam Medical Center, Haifa 31096, Israel
Key Words: stem cells • tissue engineering • human embryonic stem cells • heart failure • ion channels • arrhythmias
Address for correspondence: Prof. Lior Gepstein, M.D., Ph.D., The Shonis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine. The Bruce Rappaport Institute in the Medical Sciences, Faculty of Medicine, Technion, Israel Institute of Technology, and the Cardiology Department, Rambam Medical Center, Haifa 32000, Israel. Voice: 972-4-8295303; fax: 972-4-852-4758. e-mail: gepsteinl{at}medicine.ucsf.edu
The recent advancements in stem cell biology, molecular and cell biology, and tissue engineering have paved the way to the development of a new biomedical discipline: regenerative medicine. The heart represents an attractive candidate for this emerging discipline since these emerging technologies could be used to potentially treat a variety of myocardial disorders. Here we describe our efforts in using stem cell and cell therapy strategies to restore the myocardial electromechanical properties. Specifically, our research has focused on the potential role of human embryonic stem cells (hESC) for myocardial regeneration (for the treatment of heart failure) and on using genetically engineered cell grafts to modify the myocardial electrophysiological properties (for the treatment of cardiac arrhythmias). The recently described hESC lines are unique pluripotent cell lines that can be propagated in the undifferentiated state in culture and coaxed to differentiate into cell derivatives of all three germ layers, including cardiomyocytes. The current article describes this unique cardiomyocyte differentiating system and details the molecular, ultrastructural, and functional properties of the generated hESC-derived cardiomyocytes (hESC-CMs). The ability of the hESC-CMs to integrate structurally and functionally with host cardiomyocytes in both in vitro and in vivo studies will be described as well as their ability to restore the myocardial electromechanical function in animal models of diseased hearts. We will next present detailed in vitro, in vivo, and computer simulation studies performed in our laboratory testing the hypothesis that cell grafts, engineered to express specific ion channels, can be used to modify the myocardial electrophysiological properties of cardiac tissue. The potential and drawbacks of this novel approach for the treatment of both tachyarrhythmias (using cell grafts expressing potassium channels) and bradyarrhythmias (using hESC coaxed to differentiate into pacemaking cells or conducting tissue) will be described.
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