Improved Computational Identification of Drug Response Using Optical Measurements of Human Stem Cell Derived Cardiomyocytes in Microphysiological Systems

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 Ca 2+ 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.

Computational translation of drug effects from animal experiments to human ventricular myocytes

“…In the present study, our principal aim was to generalize the methods we have developed previously 12,13 for extrapolating drug effects obtained using hiPSC-CMs to healthy, mature human ventricular myocytes. Importantly, we found that the an equivalent approach can be used to translate measured pharmacological effects on the action potential in animal models to those in healthy adult human myocytes by employing the same models for the same currents in different cell types.…”

“…11,51,52 . In our computations, we use the Base model developed in 13 , as it systematically uses the same model for the identical ion channel in two different species. Note that in 13 the results of the Base model is compared to the results of the Paci model (for immature cells) and to the Grandi et al model and the ORd model (adult human cells).…”

“…The base model of the action potential. In all of our simulations, we use the Base model derived in 13 .…”

“…Previously 12,13 , we have developed a theoretical approach which allowed translation of measurements obtained on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to adult cardiomyocytes. In brief, we have demonstrated that after inverting hiPSC-CM data, and finding the effect of a drug candidate on every ion channel, these findings can be accurately mapped to the case of mature cardiomyocytes.…”

“…[14][15][16] with significant uncertainty. Here, in order to focus on the trans-species mapping, we use the techniques developed in 13 , simplified considerably by assuming that we know which of the ion channels that are affected by a given drug. In this simplified case it is sufficient to only have data on the transmembrane potential.…”