High Throughput Measurement of Ca++ Dynamics in Human Stem Cell-Derived Cardiomyocytes by Kinetic Image Cytometery: A Cardiac Risk Assessment Characterization Using a Large Panel of Cardioactive and Inactive Compounds
| Autor: | Jeffrey H. Price, Fabio Cerignoli, Rob Towart, David J. Gallacher, Hua Rong Lu, Ross Whittaker, Emily R. Pfeiffer, Raquel Vega |
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| Rok vydání: | 2015 |
| Předmět: |
Heart Diseases
Phenotypic screening Induced Pluripotent Stem Cells chemistry.chemical_element Action Potentials Calcium Toxicology Animal Testing Alternatives Risk Assessment Calcium in biology Cell Line Heart Rate Toxicity Tests Humans Myocytes Cardiac Calcium Signaling Induced pluripotent stem cell Ion channel Calcium signaling Image Cytometry Dose-Response Relationship Drug Chemistry Drug discovery Reproducibility of Results Anatomy Cardiotoxicity High-Throughput Screening Assays Kinetics Phenotype Biophysics Stem cell |
| Zdroj: | Toxicological sciences : an official journal of the Society of Toxicology. 148(2) |
| ISSN: | 1096-0929 |
| Popis: | Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as a powerful in vitro model for cardiac safety assessment which may allow for better identification of compounds with poor arrhythmogenic liability profiles early in the drug discovery process. Here, we describe our examination of the Kinetic Image Cytometer (KIC) system's ability to predict adverse compound effects using hiPS-CMs and a library of 53 compounds, the majority of which are known to be cardioactive compounds, and several negative controls. The KIC provides a high throughput method for analyzing intracellular calcium transients. In the cardiomyocyte, intracellular calcium transients integrate the electrochemical signals of the action potential (AP) with the molecular signaling pathways regulating contraction. Drug-induced alterations in the shape and duration of AP result in changes to the shape and duration of the intracellular calcium transient. By examining calcium transient dynamics in hiPS-CMs, KIC can be used as a phenotypic screen to assess compound effects across multiple ion channel types (MITs), detecting MITs, calcium handling and signaling effects. The results of this blinded study indicate that using hiPS-CMs, KIC is able to accurately detect drug-induced changes in Ca(2+) transient dynamics (ie, duration and beat rate) and therefore, may be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase. |
| Databáze: | OpenAIRE |
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