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Calcium Handling in Embryonic Stem Cell–Derived Cardiac Myocytes

Of Mice and Men


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.


Abstract: Excitation–contraction (EC) coupling is fundamental to the function of cardiac myocytes (CMs). In mature myocytes plasma membrane (PM) L-type Ca2+ channels function in close juxtaposition to ryanodine receptors (RyR) on the sarcoplasmic reticulum (SR) membrane. Action potentials (APs) cause the opening of PM L-type Ca2+ channels, which in turn provide trigger Ca2+ for a larger RyR-mediated SR Ca2+ release. In contrast, developing myocytes have a less well-developed SR. This incomplete development is observed in early stage and mid-maturation stages of murine embryonic stem cell–derived cardiac myocytes (ESC-CMs). Despite the absence of a well-developed t-tubule system, murine ESC-CMs use internal Ca2+ stores for EC coupling. Direct measures of Ca2+ handling, including pharmacological studies and investigation of genetically modified mouse ESC-CMs, established an important contribution of RyR-mediated internal Ca2+ store to cell function. Similarly, early-stage human ESC-CMs use internal Ca2+ store and partially share Ca2+ handling characteristics with murine ESC-CMs. For example, elementary Ca2+ release events are present in both murine and human ESC-CMs, and it is likely that Ca2+ handling contributes to automatic rhythm generation in these cells. However, in human ESC-CMs, a unique voltage-gated Na+ channel window current is critical for spontaneous, rhythmic depolarization. The advent of the murine and human ES cardiomyocyte differentiating systems has provided initial insights into the early steps of development of excitability and electromechanical coupling in the mammalian heart, including patterns of gene expression, myofibrillogenesis, ion channel development and function, and Ca2+ handling. Here we discuss the information gained from these models to describe the nexus of voltage-gated channel currents and Ca2+ handling on rhythmic activity.