Key result
In human embryonic stem cell-derived cardiomyocytes, SERCA overexpression, rather than NCX, is the main Ca2+ remover during diastole and improves immature negative-frequency/force responses.
Why the study?
The relative contribution of SERCA and NCX to Ca2+-handling in human pluripotent stem cell-derived ventricular cardiomyocytes remained unexplored despite their importance in excitation-contraction coupling.
Answers are grounded in this paper and cite their sources.
In human embryonic stem cell-derived cardiomyocytes, SERCA is a more effective cytosolic calcium remover than NCX, and its poor expression drives immature negative-frequency/force responses.
Human pluripotent stem cell (hPSCs)-derived ventricular (V) cardiomyocytes (CMs) display immature Ca 2+ –handing properties with smaller transient amplitudes and slower kinetics due to such differences in crucial Ca 2+ -handling proteins as the poor sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) pump but robust Na + -Ca 2+ exchanger (NCX) activities in human embryonic stem cell (ESC)-derived VCMs compared with adult. Despite their fundamental importance in excitation-contraction coupling, the relative contribution of SERCA and NCX to Ca 2+ -handling of hPSC-VCMs remains unexplored. We systematically altered the activities of SERCA and NCX in human embryonic stem cell-derived ventricular cardiomyocytes (hESC-VCMs) and their engineered microtissues, followed by examining the resultant phenotypic consequences. SERCA overexpression in hESC-VCMs shortened the decay of Ca 2+ transient at low frequencies (0.5 Hz) without affecting the amplitude, SR Ca 2+ content and Ca 2+ baseline. Interestingly, short hairpin RNA-based NCX suppression did not prolong the transient decay, indicating a compensatory response for Ca 2+ removal. Although hESC-VCMs and their derived microtissues exhibited negative frequency-transient/force responses, SERCA overexpression rendered them less negative at high frequencies (>2 Hz) by accelerating Ca 2+ sequestration. We conclude that for hESC-VCMs and their microtissues, SERCA, rather than NCX, is the main Ca 2+ remover during diastole; poor SERCA expression is the leading cause for immature negative-frequency/force responses, which can be partially reverted by forced expression. Combinatorial approach to mature calcium handling in hESC-VCMs may help shed further mechanistic insights. NEW & NOTEWORTHY In this study of human pluripotent stem cell-derived cardiomyocytes, we studied the role of sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) and Na + -Ca 2+ exchanger (NCX) in Ca 2+ handling. Our data support the notion that SERCA is more effective in cytosolic calcium removal than the NCX.
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Li et al. (2019) studied this question. SERCA overexpression and NCX suppression was evaluated on Ca2+ transient decay and frequency-transient/force responses. In human embryonic stem cell-derived cardiomyocytes, SERCA overexpression, rather than NCX, is the main Ca2+ remover during diastole and improves immature negative-frequency/force responses.
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