Modelling sarcomeric cardiomyopathies with human cardiomyocytes derived from induced pluripotent stem cells

Abstract

Cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) provide a unique opportunity to understand the pathophysiological effects of genetic cardiomyopathy mutations. In particular, these cells hold the potential to unmask the effects of mutations on contractile behaviour in vitro, providing new insights into genotype-phenotype relationships. With this goal in mind, several groups have established iPSC lines that contain sarcomeric gene mutations linked to cardiomyopathy in patient populations. Their studies have employed diverse systems and methods for performing mechanical measurements of contractility, ranging from single cell techniques to multicellular tissue-like constructs. Here, we review published results to date within the growing field of iPSC-based sarcomeric cardiomyopathy disease models. We devote special attention to the methods of mechanical characterization selected in each case, and how these relate to the paradigms of classical muscle mechanics. An appreciation of these somewhat subtle paradigms can inform efforts to compare the results of different studies and possibly reconcile discrepancies. Although more work remains to be done to improve and possibly standardize methods for producing, maturing, and mechanically interrogating iPSC-derived cardiomyocytes, the initial results indicate that this approach to modelling cardiomyopathies will continue to provide critical insights into these devastating diseases.

Keywords: Hypertrophic cardiomyopathy; cardiac mechanics; engineered heart tissue; iPSC-derived Cardiomyocyte; sarcomeric mutations.

Figure 1.. A survey of mechanical methods used to measure iPSC-CM contractile function from single cell to 3D engineered heart tissue