Patient-specific induced pluripotent stem cells as “disease-in-a-dish” models for inherited cardiomyopathies and channelopathies – 15 years of research

Abstract

Among inherited cardiac conditions, a special place is kept by cardiomyopathies (CMPs) and channelopathies (CNPs), which pose a substantial healthcare burden due to the complexity of the therapeutic management and cause early mortality. Like other inherited cardiac conditions, genetic CMPs and CNPs exhibit incomplete penetrance and variable expressivity even within carriers of the same pathogenic deoxyribonucleic acid variant, challenging our understanding of the underlying pathogenic mechanisms. Until recently, the lack of accurate physiological preclinical models hindered the investigation of fundamental cellular and molecular mechanisms. The advent of induced pluripotent stem cell (iPSC) technology, along with advances in gene editing, offered unprecedented opportunities to explore hereditary CMPs and CNPs. Hallmark features of iPSCs include the ability to differentiate into unlimited numbers of cells from any of the three germ layers, genetic identity with the subject from whom they were derived, and ease of gene editing, all of which were used to generate “disease-in-a-dish” models of monogenic cardiac conditions. Functionally, iPSC-derived cardiomyocytes that faithfully recapitulate the patient-specific phenotype, allowed the study of disease mechanisms in an individual-/allele-specific manner, as well as the customization of therapeutic regimen. This review provides a synopsis of the most important iPSC-based models of CMPs and CNPs and the potential use for modeling disease mechanisms, personalized therapy and deoxyribonucleic acid variant functional annotation.

Keywords: Induced pluripotent stem cells; Cardiomyopathy; Channelopathy; Genes; Mutation; Deoxyribonucleic acid variants

Core Tip: Induced pluripotent stem cell (iPSC) technology holds a great potential for medical research. Patient-specific iPSC-derived cardiomyocytes offer a unique framework for various applications, such as cardiotoxicity screening, drug discovery, disease modeling, and cell therapy. In the particular case of inherited cardiomyopathies and channelopathies, iPSC-based models have prompted study of disease mechanisms in an individual-/allele-specific manner, as well as the customization of therapeutic regimens. Herein, we present and critically discuss the current knowledge and key experimental approaches that support patient-specific iPSCs as robust “disease-in-a-dish” models for genetic cardiomyopathies and channelopathies after 15 years of research.