hiPSC-CM Monolayer Maturation State Determines Drug Responsiveness in High Throughput Pro-Arrhythmia Screen

• Published in: Scientific reports Vol. 7; no. 1; pp. 13834 - 12
• Main Authors: da Rocha, André Monteiro, Campbell, Katherine, Mironov, Sergey, Jiang, Jiang, Mundada, Lakshmi, Guerrero-Serna, Guadalupe, Jalife, José, Herron, Todd J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-10-2017; Nature Publishing Group
• Subjects: 13; 14; 14/34; 631/154/1438; 631/1647/2163; 9/10; Action Potentials; Arrhythmia; Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - metabolism; Cardiac arrhythmia; Cardiomyocytes; Cardiotoxicity; Cells, Cultured; Drug development; Drug Discovery; Drug Evaluation, Preclinical - methods; Drug screening; Fetuses; High-Throughput Screening Assays - methods; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Maturation; multidisciplinary; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Pluripotency; Science; Science (multidisciplinary); Small Molecule Libraries - pharmacology; Stem cells
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-13590-y

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) offer a novel
in vitro
platform for pre-clinical cardiotoxicity and pro-arrhythmia screening of drugs in development. To date hiPSC-CMs used for cardiotoxicity testing display an immature, fetal-like cardiomyocyte structural and electrophysiological phenotype which has called into question the applicability of hiPSC-CM findings to the adult heart. The aim of the current work was to determine the effect of cardiomyocyte maturation state on hiPSC-CM drug responsiveness. To this end, here we developed a high content pro-arrhythmia screening platform consisting of either fetal-like or mature hiPSC-CM monolayers. Compounds tested in the screen were selected based on the pro-arrhythmia risk classification (Low risk, Intermediate risk, or High risk) established recently by the FDA and major stakeholders in the Drug Discovery field for the validation of the Comprehensive
In vitro
Pro-Arrhythmia Assay (CiPA). Here we show that maturation state of hiPSC-CMs determines the absolute pro-arrhythmia risk score calculated for these compounds. Thus, the maturation state of hiPSC-CMs should be considered prior to pro-arrhythmia and cardiotoxicity screening in drug discovery programs.