Abstract
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) hold great potential for drug screening applications. However, their usefulness is limited by the relative immaturity of the cells’ electrophysiological properties as compared to native cardiomyocytes in the adult human heart. In this work, we extend and improve on methodology to address this limitation, building on previously introduced computational procedures which predict drug effects for adult cells based on changes in optical measurements of action potentials and Ca2+ transients made in stem cell derived cardiac microtissues. This methodology quantifies ion channel changes through the inversion of data into a mathematical model, and maps this response to an adult phenotype through the assumption of functional invariance of fundamental intracellular and membrane channels during maturation. Here, we utilize an updated action potential model to represent both hiPSC-CMs and adult cardiomyocytes, apply an IC50-based model of dose-dependent drug effects, and introduce a continuation-based optimization algorithm for analysis of dose escalation measurements using five drugs with known effects. The improved methodology can identify drug induced changes more efficiently, and quantitate important metrics such as IC50 in line with published values. Consequently, the updated methodology is a step towards employing computational procedures to elucidate drug effects in adult cardiomyocytes for new drugs using stem cell-derived experimental tissues.
Highlights
The development of human induced pluripotent stem cells opens promising avenues of investigation into a wide variety of fundamental questions in cell physiology and beyond [for recent reviews, see, e.g., (Yoshida and Yamanaka, 2017; Di Baldassarre et al, 2018; Ye et al, 2018)]
In the section Identification of Drug Effects on human induced pluripotent stem cells (hiPSCs)-CMs Based on Simulated Data, we use the inversion procedure to identify drug effects for data generated by simulations
In the section Identification of Drug Effects on hiPSC-CMs Based on Optical Measurements, we apply the inversion procedure to identify drug effects from data obtained from optical measurements of hiPSC-CMs
Summary
The development of human induced pluripotent stem cells (hiPSCs) opens promising avenues of investigation into a wide variety of fundamental questions in cell physiology and beyond [for recent reviews, see, e.g., (Yoshida and Yamanaka, 2017; Di Baldassarre et al, 2018; Ye et al, 2018)]. One of the more immediately tractable applications of hiPSCs is the creation of specific human cell and tissue samples to augment drug discovery and development pipelines. These pipelines have traditionally relied on animal models in key areas of testing, but are limited by significant physiological differences between animal and human cells [see, e.g., (Mathur et al, 2016; Fine and Vunjak-Novakovic, 2017; Yoshida and Yamanaka, 2017; Ye et al, 2018)]. HiPSCs are associated with a variety of scientific challenges that must be resolved to realize the full potential of the technology [see, e.g., (Mathur et al, 2015; Mathur et al, 2016; Mora et al, 2017; Christensen et al, 2018; Ronaldson-Bouchard et al, 2018; Zhao et al, 2018)]
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