A human population-based organotypic in vitro model for cardiotoxicity screening

ALTEX
Fabian Alexander GrimmIvan Rusyn

Abstract

Assessing inter-individual variability in responses to xenobiotics remains a substantial challenge, both in drug development with respect to pharmaceuticals and in public health with respect to environmental chemicals. Although approaches exist to characterize pharmacokinetic variability, there are no methods to routinely address pharmacodynamic variability. In this study, we aimed to demonstrate the feasibility of characterizing inter-individual variability in a human in vitro model. Specifically, we hypothesized that genetic variability across a population of iPSC-derived cardiomyocytes translates into reproducible variability in both baseline phenotypes and drug responses. We measured baseline and drug-related effects in iPSC-derived cardiomyocytes from 27 healthy donors on kinetic Ca2+ flux and high-content live cell imaging. Cells were treated in concentration-response with cardiotoxic drugs: isoproterenol (β-adrenergic receptor agonist/positive inotrope), propranolol (β-adrenergic receptor antagonist/negative inotrope), and cisapride (hERG channel inhibitor/QT prolongation). Cells from four of the 27 donors were further evaluated in terms of baseline and treatment-related gene expression. Reproducibility of phenotypic...Continue Reading

Citations

Jul 24, 2020·Environmental Health Perspectives·Fabian A GrimmIvan Rusyn
Oct 23, 2018·Clinical Pharmacology and Therapeutics·Alexander D BlanchetteWeihsueh A Chiu
Oct 21, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Alexander D BlanchetteWeihsueh A Chiu
Jul 16, 2021·Frontiers in Cell and Developmental Biology·Eric K N GähwilerMaximilian Y Emmert
Nov 2, 2021·The Journal of Toxicological Sciences·Nivedita Chatterjee, Xiaowei Zhang
Nov 1, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Emma C BowersShaun D McCullough

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Methods Mentioned

BETA
equilibrium dialysis
PCR
chemical treatments

Software Mentioned

MetaXpress
DESeq2
R
ImageXpress
Reactome
temposeqcount

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