Automaticity in Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells as Result of Different Mechanisms

摘要

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are nowadays one of the most studied cell types, especially for their role as in vitro models to test drug safety. Here we propose an update of our recent Paci2018 hiPSC-CM model, focusing particularly on the mechanisms underlying the action potential (AP) automaticity, i.e. one of the clearest markers of hiPSC-CM immaturity. We used two recently published formulations of the fast Na⁺ (INa) and the funny (If) currents to improve our previous fitting of in vitro experiments. We then used an optimization framework to automatically identify the parameters formalizing currents/mechanisms for which in vitro data were not available. We identified a model producing APs and Ca²⁺ transients (CaTrs) in agreement with literature and our in-house CaTr data. We showed that a strong (90%) Na⁺/Ca²⁺ exchanger (INCX) block suppresses the spontaneous APs, in agreement with in vitro data. The new Paci2019 was further validated against the in vitro experiments used for the Paci2018 model, showing that this update did not affect the capability of the new model to simulate mechanisms (e.g. responses to drugs or proarrhythmic events) successfully reproduced by the previous model. In conclusion, the Paci2019 model represents an improved tools for in silico studies e.g. on hiPSC-CM responses to drugs.