title: Human-induced pluripotent stem cell-derived cardiomyocytes exhibit temporal changes in phenotype.
abstract: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) have been recently derived and are used for basic research, cardiotoxicity assessment, and phenotypic screening. However, the hiPS-CM phenotype is dependent on their derivation, age, and culture conditions, and there is disagreement as to what constitutes a functional hiPS-CM. The aim of the present study is to characterize the temporal changes in hiPS-CM phenotype by examining five determinants of cardiomyocyte function: gene expression, ion channel functionality, calcium cycling, metabolic activity, and responsiveness to cardioactive compounds. Based on both gene expression and electrophysiological properties, at day 30 of differentiation, hiPS-CMs are immature cells that, with time in culture, progressively develop a more mature phenotype without signs of dedifferentiation. This phenotype is characterized by adult-like gene expression patterns, action potentials exhibiting ventricular atrial and nodal properties, coordinated calcium cycling and beating, suggesting the formation of a functional syncytium. Pharmacological responses to pathological (endothelin-1), physiological (IGF-1), and autonomic (isoproterenol) stimuli similar to those characteristic of isolated adult cardiac myocytes are present in maturing hiPS-CMs. In addition, thyroid hormone treatment of hiPS-CMs attenuated the fetal gene expression in favor of a more adult-like pattern. Overall, hiPS-CMs progressively acquire functionality when maintained in culture for a prolonged period of time. The description of this evolving phenotype helps to identify optimal use of hiPS-CMs for a range of research applications.
authors.affiliation: Heart Failure Discovery Performance Unit, Metabolic and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Christine Y
authors.initials: CY
authors.lastname: Ivashchenko
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Pipes
authors.forename: Irina M
authors.initials: IM
authors.lastname: Lozinskaya
authors.forename: Zuojun
authors.initials: Z
authors.lastname: Lin
authors.forename: Xu
authors.initials: X
authors.lastname: Xiaoping
authors.forename: Saul
authors.initials: S
authors.lastname: Needle
authors.forename: Eugene T
authors.initials: ET
authors.lastname: Grygielko
authors.forename: Erding
authors.initials: E
authors.lastname: Hu
authors.forename: John R
authors.initials: JR
authors.lastname: Toomey
authors.forename: John J
authors.initials: JJ
authors.lastname: Lepore
authors.forename: Robert N
authors.initials: RN
authors.lastname: Willette
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D007473:Ion Channels / Q000502:physiology; D032383:Myocytes, Cardiac / Q000145:classification / Q000166:cytology* / Q000502:physiology*; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000145:classification / Q000166:cytology* / Q000502:physiology*
chemical_list: D007473:Ion Channels
keywords: human iPS-derived cardiomyocytes/hiPS-CM; in vitro differentiation; maturation