Concise Review: Cardiac Disease Modeling Using Induced Pluripotent Stem Cells

Abstract

Genetic cardiac diseases are major causes of morbidity and mortality. Although animal models have been created to provide some useful insights into the pathogenesis of genetic cardiac diseases, the significant species differences and the lack of genetic information for complex genetic diseases markedly attenuate the application values of such data. Generation of induced pluripotent stem cells (iPSCs) from patient-specific specimens and subsequent derivation of cardiomyocytes offer novel avenues to study the mechanisms underlying cardiac diseases, to identify new causative genes, and to provide insights into the disease aetiology. In recent years, the list of human iPSC-based models for genetic cardiac diseases has been expanding rapidly, although there are still remaining concerns on the level of functionality of iPSC-derived cardiomyocytes and their ability to be used for modeling complex cardiac diseases in adults. This review focuses on the development of cardiomyocyte induction from pluripotent stem cells, the recent progress in heart disease modeling using iPSC-derived cardiomyocytes, and the challenges associated with understanding complex genetic diseases. To address these issues, we examine the similarity between iPSC-derived cardiomyocytes and their ex vivo counterparts and how this relates to the method used to differentiate the pluripotent stem cells into a cardiomyocyte phenotype. We progress to examine categories of congenital cardiac abnormalities that are suitable for iPSC-based disease modeling.

Subtype-specific promoter-driven action potential imaging for precise disease modelling and drug testing in hiPSC-derived cardiomyocytes

“…2,23 Another focus of intensive research is the integration of these cells into preclinical drug safety assays, particularly to assess QT interval prolongation. 14,24–29 While patch-clamp electrophysiology is the gold standard to assess electrical properties of hiPSC-CMs, it suffers from the major limitation of a very limited throughput, which is further restricted by the necessity to identify the CM subtype of interest based on AP morphology.…”

Can Human Pluripotent Stem Cell-Derived Cardiomyocytes Advance Understanding of Muscular Dystrophies?

“…hiPSC-CMs have been extensively used to recapitulate and study ex vivo cardiac disorders associated with conduction defects or electrocardiogram (ECG) abnormalities such as long QT syndrome (Reviewed in [116]). Importantly, these studies have demonstrated a strong correlation between results obtained with hiPSC-CMs and primary adult human CMs.…”

Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue

“…Human pluripotent stem cell (hPSC) derived cardiomyocytes (CM) represent a promising and powerful tool for anti-arrhythmic drug (AAD) screening, and have been exploited to model a growing number of arrhythmogenic cardiac electrical disorders at a single cell level 9 . Investigations have predominantly focused on diseases of the ventricles, in some part because current differentiation protocols produce predominantly ventricular-like CMs, with a small minority of atrial-like and nodal-like cells 10 .…”