Metabolic Maturation Media Improve Physiological Function of Human iPSC-Derived Cardiomyocytes

Cell Rep. 2020 Jul 21;32(3):107925. doi: 10.1016/j.celrep.2020.107925.

Abstract

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have enormous potential for the study of human cardiac disorders. However, their physiological immaturity severely limits their utility as a model system and their adoption for drug discovery. Here, we describe maturation media designed to provide oxidative substrates adapted to the metabolic needs of human iPSC (hiPSC)-CMs. Compared with conventionally cultured hiPSC-CMs, metabolically matured hiPSC-CMs contract with greater force and show an increased reliance on cardiac sodium (Na+) channels and sarcoplasmic reticulum calcium (Ca2+) cycling. The media enhance the function, long-term survival, and sarcomere structures in engineered heart tissues. Use of the maturation media made it possible to reliably model two genetic cardiac diseases: long QT syndrome type 3 due to a mutation in the cardiac Na+ channel SCN5A and dilated cardiomyopathy due to a mutation in the RNA splicing factor RBM20. The maturation media should increase the fidelity of hiPSC-CMs as disease models.

Keywords: cardiomyocyte; dilated cardiomyopathy; disease modeling; engineered heart tissues; induced pluripotent stem cells; long QT syndrome 3; maturation; physiology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism
  • Cardiac Conduction System Disease / genetics
  • Cardiac Conduction System Disease / physiopathology
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Dilated / physiopathology
  • Culture Media / pharmacology*
  • Gene Expression Regulation / drug effects
  • Heart / drug effects
  • Heart / physiopathology
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism*
  • Long QT Syndrome / genetics
  • Long QT Syndrome / physiopathology
  • Membrane Potentials / drug effects
  • Models, Biological
  • Myocardial Contraction / drug effects
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Phenotype
  • Tissue Engineering

Substances

  • Culture Media
  • Calcium

Supplementary concepts

  • Long QT syndrome type 3