3D engineered cardiac tissue models of human heart disease: learning more from our mice

Abstract

Mouse engineered cardiac tissue constructs (mECTs) are a new tool available to study human forms of genetic heart disease within the laboratory. The cultured strips of cardiac cells generate physiologic calcium transients and twitch force, and respond to electrical pacing and adrenergic stimulation. The mECT can be made using cells from existing mouse models of cardiac disease, providing a robust readout of contractile performance and allowing a rapid assessment of genotype-phenotype correlations and responses to therapies. mECT represents an efficient and economical extension to the existing tools for studying cardiac physiology. Human ECTs generated from iPSCMs represent the next logical step for this technology and offer significant promise of an integrated, fully human, cardiac tissue model.

Fig. 1. Mouse ECT structure

(A) mECT suspended from tabs and submerged in growth media within a 6-well FlexCell tissue culture plate. (B) mECT mounted by sutures to a force transducer in an open perfusion chamber. Electrodes seen along upper and lower margins of chamber. Length of mECT approximately 1 cm, width 0.8 mm. (C) mECT labeled with anti-myosin binding protein C antibody (red) and DAPI nuclear counter stain (blue) showing alignment of cells with long axis of ECT and striated cardiomyocytes.

Fig. 2. Mouse ECT twitch force and calcium transients: representative contractile data from mECT

(A and B) Frank–Starling relationship with increasing force magnitude with increasing strain. (C) mECT responds to dobutamine with increased force magnitude and accelerated twitch kinetics. (D) simultaneous Fura2AM measured calcium transient and twitch force with superimposed dF/dT tracing demonstrating the relationship between the calcium transient and twitch force.