title: IK1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes.
abstract: Currently available induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) do not ideally model cellular mechanisms of human arrhythmic disease due to lack of a mature action potential (AP) phenotype. In this study, we create and characterize iPS-CMs with an electrically mature AP induced by potassium inward rectifier (IK1) enhancement. The advantages of IK1-enhanced iPS-CMs include the absence of spontaneous beating, stable resting membrane potentials at approximately -80 mV and capability for electrical pacing. Compared with unenhanced, IK1-enhanced iPS-CMs calcium transient amplitudes were larger (P < 0.05) with a typical staircase pattern. IK1-enhanced iPS-CMs demonstrated a twofold increase in cell size and membrane capacitance and increased DNA synthesis compared with control iPS-CMs (P < 0.05). Furthermore, IK1-enhanced iPS-CMs expressing the F97C-CAV3 long QT9 mutation compared with wild-type CAV3 demonstrated an increase in AP duration and late sodium current. IK1-enhanced iPS-CMs represent a more mature cardiomyocyte model to study arrhythmia mechanisms.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin, Madison, Wisconsin.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vaidyanathan
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin, Madison, Wisconsin.
authors.forename: Yogananda S
authors.initials: YS
authors.lastname: Markandeya
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin, Madison, Wisconsin.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kamp
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin, Madison, Wisconsin.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin, Madison, Wisconsin.
authors.forename: Craig T
authors.initials: CT
authors.lastname: January
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin, Madison, Wisconsin lle@medicine.wisc.edu.
authors.forename: Lee L
authors.initials: LL
authors.lastname: Eckhardt
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*
keywords: LQTS; arrhythmia; iPS-CM; potassium ion channel