Human-induced pluripotent stem cell-derived cardiomyocytes exhibit temporal changes in phenotype

Am J Physiol Heart Circ Physiol. 2013 Sep 15;305(6):H913-22. doi: 10.1152/ajpheart.00819.2012. Epub 2013 Jul 5.

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.

Keywords: human iPS-derived cardiomyocytes/hiPS-CM; in vitro differentiation; maturation.

MeSH terms

  • Action Potentials / physiology*
  • Calcium Signaling / physiology*
  • Cell Differentiation / physiology
  • Cell Line
  • Gene Expression Regulation, Developmental / physiology*
  • Humans
  • Ion Channels / physiology
  • Myocytes, Cardiac / classification
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / physiology*
  • Phenotype
  • Pluripotent Stem Cells / classification
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / physiology*

Substances

  • Ion Channels