Calcium signaling in human stem cell-derived cardiomyocytes: Evidence from normal subjects and CPVT afflicted patients

•Specific carboxyl-tail fragments of L-type Ca2+ channel maybe responsible for the voltage-dependence of cardiac CICR.•Ca2+ signaling in human fibroblast-derived cardiomyocytes shows similar voltage-dependence of CICR and Ca2+ spark properties as those of adult mammalian cardiomyocytes.•CPVT mutants myocytes of N-terminal and cytoplasmic-domains show smaller Ca2+ stores but longer, wandering, and recurrent Ca2+ sparks.•Myocytes expressing different point mutations express varied Ca2+ signaling phenotypes and pharmacological sensitivity.

Derivation of cardiomyocyte cell lines from human fibroblasts (induced pluripotent stem cells, iPSCs) has made it possible not only to investigate the electrophysiological and Ca2+ signaling properties of these cells, but also to determine the altered electrophysiological and Ca2+-signaling profiles of such cells lines derived from patients expressing mutation-inducing pathologies. This approach has the potential of generating in vitro human models of cardiovascular diseases where cellular pathology can be investigated in detail and possibly specific pharmacotherapy developed. Although this approach has been applied to a number of mutations in channel proteins that cause arrhythmias, there are only few detailed reports addressing Ca2+ signaling pathologies beyond measurements of Ca2+ transients in intact non-voltage clamped cells. Unfortunately, full understanding of Ca2+ signaling pathologies remains elusive, not only because of the plethora of Ca2+ signaling proteins defects that cause arrhythmias and cardiomyopathies, but also because detailed functional properties of Ca2+ signaling proteins are difficult to obtain. Catecholaminergic polymorphic ventricular tachycardia (CPVT1) is a malignant inherited arrhythmogenic disorder predominantly caused by mutations in the cardiac ryanodine receptor (RyR2). Thus far over 150 mutations in RyR2 have been identified that appear to cause this arrhythmia, a number of which have been expressed and studied in transgenic mice or cell-line models. The development of human iPSC-technology makes it possible to create human heart cell-lines carrying these mutations, making detailed identification of Ca2+ signaling defects and its specific pharmacotherapy possible.In this review we shall first briefly summarize the essential characteristics of the mammalian cardiac Ca2+ signaling, then compare them to Ca2+ signaling phenotypes of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) and to those of rat neonatal cardiomyocytes, and categorize the possible variance in Ca2+ signaling defects caused by different CPVT-inducing mutations as expressed in hiPSC-CMs.

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