The Comparison Between Two Mathematical Contractile Elements Integrated into an hiPSC-CM In-silico Model

摘要

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a valuable tool for in vitro drug testing and disease studies. As contractility has become one of the main experimental outputs, hiPSC-CMs in silico models should also feature the mechanisms of force generation. Thus, we integrated two contractile elements (CE), Rice2008 and Negroni2015, into Paci2020 hiPSC-CM model. The simulated force-Ca^{2+ relationships from skinned versions of the CEs revealed rather close pCa₅₀ values for both CEs: 6.17 and 6.10, respectively for Rice2008 and Negroni2015. However, Hill's coefficients for the two curves were 7.30 and 3.6. The relationships agreed with in vitro data from human engineered heart tissues. Most of the biomarkers measured from simulated spontaneous action potentials (APs) and Ca2+ transients (CaTs) showed good agreement with in vitro data for both CEs. The active peak force observed in paced conditions (1 Hz) and at extracellular Ca2+ concentration ([Ca2+]_o) of 1.8 mM was 0.011 nM/mm2 for Paci2020+Rice2008 and 0.57 mN/mm2 for Paci2020+Negroni2015. These values match, qualitatively with the 0.26 mN/mm2 peak force reported previously in vitro at [Ca2+]_o=1.8 mM Our results set an opening to develop more sophisticated hiPSC-CM models featuring both electrophysiology and biomechanics.}