Abstract
The growing importance of human induced pluripotent stem cell-derived cardiomyoyctes (hiPSC-CMs), as patient-specific and disease-specific models for studying cellular cardiac electrophysiology or for preliminary cardiotoxicity tests, generated better understanding of hiPSC-CM biophysical mechanisms and great amount of action potential and calcium transient data. In this paper, we propose a new hiPSC-CM in silico model, with particular attention to Ca2+ handling. We used (i) the hiPSC-CM Paci2013 model as starting point, (ii) a new dataset of Ca2+ transient measurements to tune the parameters of the inward and outward Ca2+ fluxes of sarcoplasmic reticulum, and (iii) an automatic parameter optimization to fit action potentials and Ca2+ transients. The Paci2018 model simulates, together with the typical hiPSC-CM spontaneous action potentials, more refined Ca2+ transients and delayed afterdepolarizations-like abnormalities, which the old Paci2013 was not able to predict due to its mathematical formulation. The Paci2018 model was validated against (i) the same current blocking experiments used to validate the Paci2013 model, and (ii) recently published data about effects of different extracellular ionic concentrations. In conclusion, we present a new and more versatile in silico model, which will provide a platform for modeling the effects of drugs or mutations that affect Ca2+ handling in hiPSC-CMs.
Highlights
Human induced pluripotent stem cell-derived cardiomyocytes are cardiac cells derived from stem cells, which have been produced by donor’s differentiated cells by means of reprogramming (Takahashi et al, 2007)
The automatic optimization process provided a new set of parameters, which is reported in Table 1, fourth column
It shows that the Ca2+ release from sarcoplasmic reticulum (SR) is not directly dependent on the ICaL activation, but on the cytosolic Ca2+ concentration Cai, which rules the behavior of the RyRo, RyRc, and RyRa gating variables
Summary
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are cardiac cells derived from stem cells, which have been produced by donor’s differentiated cells by means of reprogramming (Takahashi et al, 2007). As an in vitro human model, hiPSC-CMs strongly impacted the study of biophysical mechanisms underlying cardiac electrophysiology at cellular level, both in control and diseased conditions. During the last 10 years, many progresses were done in terms of efficiency of hiPSC-CM production and availability of commercial cell lines. This enabled the hiPSC-CM electrophysiological and pharmacological evaluation by means of medium-throughput (Rajamohan et al, 2016) or even highthroughput systems (Entcheva and Bub, 2016; Klimas et al., 2016), where the use of voltage- and calcium-sensitive dyes has been combined with hiPSC-CM optogenetic stimulation
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