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hiPSC-CM Monolayer Maturation State Determines Drug Responsiveness in High Throughput Pro-Arrhythmia Screen.
- Source :
-
Scientific reports [Sci Rep] 2017 Oct 23; Vol. 7 (1), pp. 13834. Date of Electronic Publication: 2017 Oct 23. - Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- Action Potentials
Arrhythmias, Cardiac metabolism
Cells, Cultured
Humans
Induced Pluripotent Stem Cells cytology
Induced Pluripotent Stem Cells metabolism
Myocytes, Cardiac cytology
Myocytes, Cardiac metabolism
Arrhythmias, Cardiac chemically induced
Drug Discovery
Drug Evaluation, Preclinical methods
High-Throughput Screening Assays methods
Induced Pluripotent Stem Cells drug effects
Myocytes, Cardiac drug effects
Small Molecule Libraries pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 29061979
- Full Text :
- https://doi.org/10.1038/s41598-017-13590-y