Population-based mechanistic modeling allows for quantitative predictions of drug responses across cell types

Gong, Jingqi Q. X.; Sobie, Eric A.

doi:10.1038/s41540-018-0047-2

Cited by 65 publications

(84 citation statements)

References 53 publications

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“…Translation between iPSC-CM and adult phenotypes will be critical with respect to the use of iPSC-CMs for drug safety and discovery in the human population. Gong & Sobie (2018) have developed a cross-cell type regression model that translates response to ionic current perturbations in an iPSC-CM model to the predicted the response in an adult ventricular cardiomyocyte model. Additionally, Tveito et al (2018) have developed a method of utilizing optically obtained experimental whole-cell drug-response data from immature iPSC-CMs to computationally predict the effect in a mature iPSC-CM phenotype, which serves as a more representative model of adult cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

A computational model of induced pluripotent stem‐cell derived cardiomyocytes incorporating experimental variability from multiple data sources

Kernik

Morotti

et al. 2019

The Journal of Physiology

104

128

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Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) capture patient-specific genotype-phenotype relationships, as well as cell-to-cell variability of cardiac electrical activity r Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and also identify vulnerable parameter regimes r We have developed a whole-cell model of iPSC-CMs, composed of single exponential voltage-dependent gating variable rate constants, parameterized to fit experimental iPSC-CM outputs r We have utilized experimental data across multiple laboratories to model experimental variability and investigate subcellular phenotypic mechanisms in iPSC-CMs r This framework links molecular mechanisms to cellular-level outputs by revealing unique subsets of model parameters linked to known iPSC-CM phenotypes Abstract There is a profound need to develop a strategy for predicting patient-to-patient vulnerability in the emergence of cardiac arrhythmia. A promising in vitro method to address patient-specific proclivity to cardiac disease utilizes induced pluripotent stem cell-derived Divya Kernik is currently a PhD candidate in Biomedical Engineering at the University of California, Davis. She obtained a BS in Biomedical Engineering from Johns Hopkins University. The focus of her PhD work has been the development of computational methods that help to understand human-derived cardiac cells, as reported in the present study. In the future, she aims to continue to use computational modelling to address questions in cardiac physiology and pharmacology, with the underlying goal of incorporating human diversity throughout these efforts.

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Section: Discussionmentioning

confidence: 99%

A computational model of induced pluripotent stem‐cell derived cardiomyocytes incorporating experimental variability from multiple data sources

Kernik

Morotti

et al. 2019

The Journal of Physiology

104

128

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“…While there is no analog of the HMDP for human, or other species (such as rabbit, dog, or pig) with AP features similar to human, it might be possible to extend the present study using renewable cardiomyocytes (CMs) derived from induced pluripotent stem cells (iPSC) as an alternative to the HMDP. However, iPSC-CMs and adult myocytes isolated from intact hearts exhibit quantitative differences in their responses to ionic current perturbations ( Gong and Sobie, 2018 ). Therefore, it is unclear whether the variation of ionic conductances in iPSC-CMs of genetically different subjects would be representative of the variation of conductances in intact hearts of the same subjects, which is ultimately relevant for pharmacological treatment of cardiac arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

The Ca2+ transient as a feedback sensor controlling cardiomyocyte ionic conductances in mouse populations

Rees

Yang

Santolini

et al. 2018

eLife

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Conductances of ion channels and transporters controlling cardiac excitation may vary in a population of subjects with different cardiac gene expression patterns. However, the amount of variability and its origin are not quantitatively known. We propose a new conceptual approach to predict this variability that consists of finding combinations of conductances generating a normal intracellular Ca2+ transient without any constraint on the action potential. Furthermore, we validate experimentally its predictions using the Hybrid Mouse Diversity Panel, a model system of genetically diverse mouse strains that allows us to quantify inter-subject versus intra-subject variability. The method predicts that conductances of inward Ca2+ and outward K+ currents compensate each other to generate a normal Ca2+ transient in good quantitative agreement with current measurements in ventricular myocytes from hearts of different isogenic strains. Our results suggest that a feedback mechanism sensing the aggregate Ca2+ transient of the heart suffices to regulate ionic conductances.

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“…hiPSC-CMs and adult ventricular CMs show qualitatively consistent responses to some, but not all drugs (9,20,30). Recently, two computational studies (8,31) quantitatively reported on the main electrophysiological differences between hiPSC-CM and adult ventricular CMs by comparing the Paci 2013 and O'Hara-Rudy models. Paci et al (22) investigated the discrepancies between hiPSC-CM and adult ventricular CMs by simulating the effects of pharmaceutical block of several membrane currents.…”

Section: Toward a Mature Electrophysiological Phenotypementioning

confidence: 99%

Required G1 to Suppress Automaticity of iPSC-CMs Depends Strongly on I1 Model Structure

Fabbri

Goversen

Vos

et al. 2019

Biophysical Journal

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Human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) are a virtually endless source of human cardiomyocytes that may become a great tool for safety pharmacology; however, their electrical phenotype is immature: they show spontaneous action potentials (APs) and an unstable and depolarized resting membrane potential (RMP) because of lack of I K1 . Such immaturity hampers their application in assessing drug safety. The electronic overexpression of I K1 (e.g., through the dynamic clamp (DC) technique) is an option to overcome this deficit. In this computational study, we aim to estimate how much I K1 is needed to bring hiPSC-CMs to a stable and hyperpolarized RMP and which mathematical description of I K1 is most suitable for DC experiments. We compared five mature I K1 formulations (Bett, Dhamoon, Ishihara, O'Hara-Rudy, and ten Tusscher) with the native one (Paci), evaluating the main properties (outward peak, degree of rectification), and we quantified their effects on AP features (RMP, _ V max , APD 50 , APD 90 (AP duration at 50 and 90% of repolarization), and APD 50 /APD 90 ) after including them in the hiPSC-CM mathematical model by Paci. Then, we automatically identified the critical conductance for I K1 ( G K1, critical ), the minimally required amount of I K1 suppressing spontaneous activity. Preconditioning the cell model with depolarizing/hyperpolarizing prepulses allowed us to highlight time dependency of the I K1 formulations. Simulations showed that inclusion of mature I K1 formulations resulted in hyperpolarized RMP and higher _ V max , and observed G K1, critical and the effect on AP duration strongly depended on I K1 formulation. Finally, the Ishihara I K1 led to shorter (À16.3%) and prolonged (þ6.5%) APD 90 in response to hyperpolarizing and depolarizing prepulses, respectively, whereas other models showed negligible effects. Fine-tuning of G K1 is an important step in DC experiments. Our computational work proposes a procedure to automatically identify how much I K1 current is required to inject to stop the spontaneous activity and suggests the use of the Ishihara I K1 model to perform DC experiments in hiPSC-CMs. SIGNIFICANCE In this work, we aim to contribute a method that will facilitate automated dynamic clamp (DC) experiments in which I K1 is injected in induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs). By introducing G K1, critical (minimal I K1 conductance needed to stop automaticity of iPSC-CMs), we are proposing a different approach to setting up DC experiments. These are usually based on the injection of a fixed current density. In contrast, G K1, critical is a parameter that depends on the cell under investigation. Our in silico approach analyzed analogies and differences between I K1 formulations without the confounding factor that can be brought by the variability of iPSC-CMs. It highlighted how much the employed mathematical formulation of I K1 can affect G K1, critical and the action potential waveform in DC experiments.

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Population-based mechanistic modeling allows for quantitative predictions of drug responses across cell types

Cited by 65 publications

References 53 publications

A computational model of induced pluripotent stem‐cell derived cardiomyocytes incorporating experimental variability from multiple data sources

A computational model of induced pluripotent stem‐cell derived cardiomyocytes incorporating experimental variability from multiple data sources

The Ca2+ transient as a feedback sensor controlling cardiomyocyte ionic conductances in mouse populations

Required G1 to Suppress Automaticity of iPSC-CMs Depends Strongly on I1 Model Structure

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