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

Abstract

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 Ca 2+ 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 Ca 2+ concentration ([Ca 2+ ]o) of 1.8 mM was 0.011 mN/mm 2 for Paci2020+Rice2008 and 0.57 mN/mm 2 for Paci2020+Negroni2015. These values match, qualitatively with the 0.26 mN/mm 2 peak force reported previously in vitro at [Ca 2+ ]o=1.8 mM. Our results set an opening to develop more sophisticated hiPSC-CM models featuring both electrophysiology and biomechanics.

A mathematical model of hiPSC cardiomyocytes electromechanics

“…The assessment of the contractility is crucial when developing a mathematical cell model of cardiac electromechanics (Campbell et al, 2008 ; Forouzandehmehr et al, 2020 ; Margara et al, 2020 , 2021 ; Negroni et al, 2015 ; Pioner et al, 2020 ; Rice et al, 2008 ; Tran et al, 2017 ; Zile & Trayanova, 2017 ). In that context, the tension–SL relationship is not only a standard experimental protocol in myofilament studies (Negroni et al, 2015 ; Rice et al, 2008 ) but also serves as a measure for evaluating the CE mathematical models.…”