Computational Study of the Excitation of Human Induced Pluripotent Stem-Cell Derived Cardiomyocytes

Abstract

Human induced pluripotent stem-cell derived cardiomyocytes (hiPSC-CMs) have proven to be a revolutionary advance for tissue engineering, disease modeling, and drug testing and discovery. Computational modeling enables a detailed electrophysiological analysis that is otherwise difficult or impossible to achieve under strictly experimental settings. Action potential characteristics of hiPSC-CMs measured in our lab at four different pacing rates were used it to modify the computational Kernik-Clancy hiPSC-CM model. The modified model was used to compare the excitation of single hiPSC-CMs with that of single human ventricular cardiomyocytes (hV-CMs) under varying conditions, including at stimulation at different strengths, rates and pulse durations. The physiological stimulation of both hiPSC-CMs and hV-CMs embedded within a tissue strand involves a biphasic waveform during which time excitatory currents (particularly INa, but also ICaT and ICaL for hiPSC-CMs and INaL and ICaL for hV-CMs) are activated during both phases of the waveform. INa in particular activated more slowly and with diminished amplitude under conditions of increasing pacing rate or increasing intracellular resistance. Lastly, histograms characterizing the relative amounts of excitatory currents in a population of hiPSC-CMs become broader with increasing levels of INa block, with ICaT and ICaL working in tandem to excite cells where INa has failed to activate. In general, hiPSC-CMs were found to be more excitable from rest compared with hV-CMs owing to their more depolarized resting potential and intrinsic automaticity despite a lower sodium channel density. Such a mismatch should be taken into consideration for applications using these cells, particularly for cardiac repair. Key PointsO_LICardiomyocytes (CMs) generated from human stem cells derived from blood or skin have great potential for cardiac repair, safety pharmacology and disease modeling, but understanding their excitability is crucial for their proper application. C_LIO_LIComputational modeling reveals greater excitability of these cells in terms of various metrics compared with that of human adult ventricular CMs at multiple pacing rates. C_LIO_LIThe excitation of CMs within a strand differs substantially from that usually used to study single isolated CMs and is dissected in terms of the underlying ionic currents. C_LIO_LIComputational modeling also predicts how a heterogeneous population of stem cell-derived CMs and their underlying ionic currents could respond to varying levels of reduced sodium current. C_LIO_LIOur study presents a cautionary note for applications using these cells, particularly for cardiac repair. C_LI