Deep phenotyping of human induced pluripotent stem cell-derived atrial and ventricular cardiomyocytes

JCI Insight. 2018 Jun 21;3(12):e99941. doi: 10.1172/jci.insight.99941.


Generation of homogeneous populations of subtype-specific cardiomyocytes (CMs) derived from human induced pluripotent stem cells (iPSCs) and their comprehensive phenotyping is crucial for a better understanding of the subtype-related disease mechanisms and as tools for the development of chamber-specific drugs. The goals of this study were to apply a simple and efficient method for differentiation of iPSCs into defined functional CM subtypes in feeder-free conditions and to obtain a comprehensive understanding of the molecular, cell biological, and functional properties of atrial and ventricular iPSC-CMs on both the single-cell and engineered heart muscle (EHM) level. By a stage-specific activation of retinoic acid signaling in monolayer-based and well-defined culture, we showed that cardiac progenitors can be directed towards a highly homogeneous population of atrial CMs. By combining the transcriptome and proteome profiling of the iPSC-CM subtypes with functional characterizations via optical action potential and calcium imaging, and with contractile analyses in EHM, we demonstrated that atrial and ventricular iPSC-CMs and -EHM highly correspond to the atrial and ventricular heart muscle, respectively. This study provides a comprehensive understanding of the molecular and functional identities characteristic of atrial and ventricular iPSC-CMs and -EHM and supports their suitability in disease modeling and chamber-specific drug screening.

Keywords: Expression profiling; Muscle Biology; Proteomics; Stem cells; iPS cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Diagnostic Imaging / methods
  • Drug Evaluation, Preclinical
  • Heart Ventricles / cytology*
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Isotope Labeling
  • Myocardium
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Proteome
  • Transcriptome
  • Tretinoin


  • Proteome
  • Tretinoin
  • Calcium