title: Evaluation of Batch Variations in Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes from 2 Major Suppliers.
abstract: Drug-induced proarrhythmia is a major safety issue in drug development. Developing sensitive in vitro assays that can predict drug-induced cardiotoxicity in humans has been a challenge of toxicology research for decades. Recently, induced pluripotent stem cell-derived human cardiomyocytes (iPSC-hCMs) have become a promising model because they largely replicate the electrophysiological behavior of human ventricular cardiomyocytes. Patient-specific iPSC-hCMs have been proposed for personalized cardiac drug selection and adverse drug response prediction; however, many procedures are involved in cardiomyocytes differentiation and purification process, which may result in large line-to-line and batch-to-batch variations. Here, we examined the purity, cardiac ion channel gene expression profile, and electrophysiological response of 3 batches of iPSC-hCMs from each of 2 major cell suppliers. We found that iPSC-hCMs from both vendors had similar purities. Most of the cardiac ion channel genes were expressed uniformly among different batches of iCells, while larger variations were found in Cor.4U cells, particularly in the expression of CACNA1C, KCND2, and KCNA5 genes, which could underlie the differences in baseline beating rate (BR) and field potential duration (FPD) measurements. Although, in general, the electrophysiological responses of different batches of cells to Na+, Ca2+, Ikr, and Iks channel blockers were similar, with Ikr blocker-induced proarrhythmia, the sensitivities were depended on baseline BR and FPD values: cells that beat slower had longer FPD and greater sensitivity to drug-induced proarrhythmia. Careful evaluation of the performance of iPSC-hCMs and methods of data analysis is warranted for shaping regulatory standards in qualifying iPSC-hCMs for drug safety testing.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, Arkansas 72079.|Department of Cardiovascular Medicine, First Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, ShaanXI, 710061, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Huo
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, Arkansas 72079.
authors.forename: Archana
authors.initials: A
authors.lastname: Kamalakar
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, U.S. FDA, Jefferson, Arkansas 72079.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, Arkansas 72079.
authors.forename: Beverly
authors.initials: B
authors.lastname: Word
authors.affiliation: Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, U.S. FDA, Silver Spring, Maryland 20993.
authors.forename: Norman
authors.initials: N
authors.lastname: Stockbridge
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, Arkansas 72079.
authors.forename: Beverly
authors.initials: B
authors.lastname: Lyn-Cook
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, Arkansas 72079.
authors.forename: Li
authors.initials: L
authors.lastname: Pang
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D002121:Calcium Channel Blockers / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000191:economics / Q000379:methods*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015203:Reproducibility of Results; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism; D023382:Toxicity Tests, Acute / Q000191:economics / Q000379:methods*; D061567:Voltage-Gated Sodium Channel Blockers / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; C079146:CACNA1C protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; C496981:KCNA5 protein, human; C497018:KCND2 protein, human; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D051672:Shal Potassium Channels; D061567:Voltage-Gated Sodium Channel Blockers
keywords: drug-induced proarrhythmia; iPSC-CMs; batch variations.