The Role of Human-Induced Pluripotent Stem Cells in Studying Cardiac Channelopathies

Abstract

Cardiac channelopathies are inherited diseases that increase the risk of sudden cardiac death. While different genes have been associated with inherited channelopathies, there are still subtypes, e.g., catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome, where the genetic cause remains unknown. Various models, including animal models, heterologous expression systems, and the human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSCs-CMs) model, have been used to study the pathophysiological mechanisms of channelopathies. Recently, researchers have focused on using hiPSCs-CMs to understand the genotype-phenotype correlation and screen drugs. By combining innovative techniques such as Clustered Regularly Interspaced Short Palindromic Repeats/Clustered Regularly Interspaced Short Palindromic Repeats associated protein 9 (CRISPR/Cas9)-mediated genome editing, and three-dimensional (3D) engineered heart tissues, we can gain new insights into the pathophysiological mechanisms of channelopathies. This approach holds promise for improving personalized drug treatment. This review highlights the role of hiPSCs-CMs in understanding the pathomechanism of Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia and how these models can be utilized for drug screening.

Keywords: Brugada syndrome; catecholaminergic polymorphic ventricular tachycardia; sudden cardiac death.

Figure 1

Genes involved in Brugada syndrome. Chronology of the discovery of the genes linked to Brugada syndrome. The genes are classified as sodium channel, calcium channel, potassium channel genes, and genetic triggers based on their molecular interactions regarding Brugada syndrome.

Figure 2

Genes involved in catecholaminergic polymorphic ventricular tachycardia. Chronology of the discovery of the genes linked to catecholaminergic polymorphic ventricular tachycardia. The genes are classified as genes involved that regulate sarcoplasmic reticulum calcium release during excitation–contraction coupling and genes with an unknown mechanism leading to catecholaminergic polymorphic ventricular tachycardia.

Figure 3

The use of several techniques to carry out functional studies on hiPSCs-CMs. Patients are typed to the respective channelopathies based on their electrocardiogram (ECG). Biopsies are taken from patients suffering Brugada syndrome (BrS) or catecholaminergic polymorphic ventricular tachycardia (CPVT). Somatic cells are extracted from patients’ skin or blood biopsies. The somatic cells are reprogrammed to human-induced pluripotent stem cells (hiPSCs). The differentiation into hiPSCs-cardiomyocytes (hiPSCs-CMs) is induced by culturing under specific conditions. hiPSCs-CMs can be used for modeling channelopathies. Functional studies on hiPSCs-CMs include patch clamp, optical mapping, mechanics, immunohistochemistry, fluorescence imaging drug screening, multielectrode array, and impedance assays. Image created using Smart Servier Medical Art.