Combination of Functional Cardiomyocytes Derived from Human Stem Cells and a Highly-Efficient Microelectrode Array System: An Ideal Hybrid Model Assay for Drug Development

Abstract

Human pluripotential stem cells including both embryonic stem cells (hESC) and induced pluripotent stem cells (hiPSC) possess self-renewing potency and pluripotentency and can differentiate into virtually any somatic cell type. These features are a distinct advantage for the generation of specific types of human tissue cells in vitro for continuous use in drug development. Recently, an assay system for drug-induced QT interval prolongation using hESC/hiPSC-derived cardiomyocytes and microelectrode arrays (MEA) has been developed. Drug-induced QT interval prolongation (DIQTIP) can lead to sudden cardiac death and is a major safety concern for the drug industry. Regulatory authorities such as the US FDA and the European Medicines Agency require in-vitro testing of all drug candidates to identify potential risk of DIQTIP prior to clinical trials. To reduce the risk of DIQTIP, a routine assay system for in vitro electrophysiological properties using cell-based assays is effective and necessary in early phase of drug discovery. This review discusses developments over the last couple of years for a qualified drug testing method and provides some examples of how hESC/hiPSC-derived cardiomyocytes are beginning to find a practical use for drug discovery and development.

The Electrophysiological Effects of Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and in Guinea Pig Isolated Hearts

“…Na + , L-type Ca 2+ , hERG and I Ks ) as well as the action of modulators of , -adrenergic and muscarinic receptors [8][9][10]. These results demonstrate the value of MEA as a novel cellular electrophysiology platform suitable to screen for deleterious cardioactive properties of drugs in discovery [11][12][13].…”

Detection of Thalidomide Embryotoxicity by In Vitro Embryotoxicity Testing Based on Human iPS Cells

“…This may be due to species barrier-related differences between rodents and humans. The effects of thalidomide (6,7). Therefore, we tried to study the teratogenic potential of thalidomide using hiPSCs instead of mouse ES cells.…”

Efficient Integration of Transgenes and Their Reliable Expression in Human Embryonic Stem Cells

“…Public-private collaborations such as Stem Cells for Safer Medicine or Stem Cells and Drug Discovery Institute have been launched to enable consistent differentiation of stem cells into particular cell types with physiologically relevant phenotypes suitable for toxicology testing. Cardiomyocytes derived from human ES/iPS cells have already begun to be used for drug-induced cardiotoxicity screening (Asai et al, 2010). In the drug development process, it is necessary to evaluate the metabolism of the novel compound in hepatocytes, because the liver is the main detoxification organ in the body.…”