Modeling Inherited Arrhythmia Disorders Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

Inherited arrhythmia disorders are a group of potentially lethal diseases that remain diagnostic and management challenges. While the genetic basis for many of these disorders is well known, the pathogenicity of individual mutations and the resulting clinical outcomes are difficult to predict. Treatment options remain imperfect, and optimizing therapy for individual patients can be difficult. Recent advances in the derivation of induced pluripotent stem cells (iPSCs) from patients and creation of genetically engineered human models using CRISPR/Cas9 has the potential to dramatically advance translational arrhythmia research. In this review, we discuss the current state of modeling inherited arrhythmia disorders using human iPSC-derived cardiomyocytes. We also discuss current limitations and areas for further study.

The Emergence of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform to Model Arrhythmogenic Diseases

“…Rapidly advancing genome editing tools including clustered regularly interspaced short palindromic repeats (CRISPR/Cas9), zinc finger nucleases (ZFN), adenoviral vectors, and transcription activator-like effector nucleases (TALEN) can significantly reduce the time and effort it takes to generate human cell lines carrying specific gene mutations or other variants with rare off-target mutagenesis [151][152][153][154][155][156][157]. Cellular genome editing has already established itself as a powerful tool and as an alternative to animal models to investigate pathophysiological mechanisms in various cardiac diseases [129,136,155,156,158].…”

“…Genome editing provides the unique opportunity to study disease modifying variants in the same genetic background. In contrast to patient-specific hiPSC, this potentially reduces the influence of epigenetic modifications and other genetic modifiers such as environmental factors on the pathophysiological phenotype [1,158]. For example, Wang et al used the zinc finger nuclease (ZFN) technology to introduce KCNQ1 and KCNH2 dominant negative mutations in hiPSC-CMs generated from healthy donors [130].…”

Insights Into the Pathogenesis of Catecholaminergic Polymorphic Ventricular Tachycardia From Engineered Human Heart Tissue

“…The advent of induced pluripotent stem cell (iPSC) technology and efficient methods to differentiate iPSCs to cardiomyocytes (iPSC-CMs) have created exciting opportunities to study inherited arrhythmias. 9 iPSC-CMs have been generated from patients with CPVT 5,[10][11][12][13] as well as other inherited arrhythmias and have been shown to capture key features of these diseases, including abnormal action potential duration and drug responses. 9 However, current iPSC-CM models of arrhythmia have been limited to isolated cells or cell clusters, leaving a large gap to modeling clinical arrhythmias, which are the emergent properties of cells assembled into myocardial tissue.…”

“…9 iPSC-CMs have been generated from patients with CPVT 5,[10][11][12][13] as well as other inherited arrhythmias and have been shown to capture key features of these diseases, including abnormal action potential duration and drug responses. 9 However, current iPSC-CM models of arrhythmia have been limited to isolated cells or cell clusters, leaving a large gap to modeling clinical arrhythmias, which are the emergent properties of cells assembled into myocardial tissue. 14 We [15][16][17] and others 18 have developed engineered cardiac microphysiological systems that induce stem cell-derived and primary cardiomyocytes to adopt native-like laminar tissue architecture, permitting tissue level measurement of contractility.…”

Cardiac Subtype-Specific Modeling of Kv1.5 Ion Channel Deficiency Using Human Pluripotent Stem Cells

“…Channelopathies in particular are amenable to disease modeling using patient-derived or genetically engineered human induced pluripotent stem cells (hiPSCs), as they tend to mediate relevant phenotypes in a cell-automomous manner (Zhang et al, 2014 ; Bezzerides et al, 2016 ; Malan et al, 2016 ). Hence, despite the fact that AF penetrance and progression is undoubtedly linked to the organismal context, hiPSC-based AF models may allow for investigating disease phenotypes and drug responses at the cellular and tissue levels.…”