Human engineered heart tissue as a model system for drug testing

Adv Drug Deliv Rev. 2016 Jan 15;96:214-24. doi: 10.1016/j.addr.2015.05.010. Epub 2015 May 27.

Abstract

Drug development is time- and cost-intensive and, despite extensive efforts, still hampered by the limited value of current preclinical test systems to predict side effects, including proarrhythmic and cardiotoxic effects in clinical practice. Part of the problem may be related to species-dependent differences in cardiomyocyte biology. Therefore, the event of readily available human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) has raised hopes that this human test bed could improve preclinical safety pharmacology as well as drug discovery approaches. However, hiPSC-CM are immature and exhibit peculiarities in terms of ion channel function, gene expression, structural organization and functional responses to drugs that limit their present usefulness. Current efforts are thus directed towards improving hiPSC-CM maturity and high-content readouts. Culturing hiPSC-CM as 3-dimensional engineered heart tissue (EHT) improves CM maturity and anisotropy and, in a 24-well format using silicone racks, enables automated, multiplexed high content readout of contractile function. This review summarizes the principal technology and focuses on advantages and disadvantages of this technology and its potential for preclinical drug screening.

Keywords: Cardiac safety pharmacology; Drug development; Engineered heart tissue; Human induced pluripotent stem cell derived cardiomyocytes; Maturation; Screening assays.

Publication types

  • Review

MeSH terms

  • Action Potentials / drug effects*
  • Animals
  • Drug Evaluation, Preclinical / methods*
  • Heart / drug effects*
  • Heart / physiology
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / drug effects*
  • Induced Pluripotent Stem Cells / physiology
  • Myocardial Contraction / drug effects
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / physiology
  • Species Specificity
  • Tissue Engineering / methods*