Modelling inherited cardiac disease using human induced pluripotent stem cell-derived cardiomyocytes: progress, pitfalls, and potential

Abstract

In the past few years, the use of specific cell types derived from induced pluripotent stem cells (iPSCs) has developed into a powerful approach to investigate the cellular pathophysiology of numerous diseases. Despite advances in therapy, heart disease continues to be one of the leading causes of death in the developed world. A major difficulty in unravelling the underlying cellular processes of heart disease is the extremely limited availability of viable human cardiac cells reflecting the pathological phenotype of the disease at various stages. Thus, the development of methods for directed differentiation of iPSCs to cardiomyocytes (iPSC-CMs) has provided an intriguing option for the generation of patient-specific cardiac cells. In this review, a comprehensive overview of the currently published iPSC-CM models for hereditary heart disease is compiled and analysed. Besides the major findings of individual studies, detailed methodological information on iPSC generation, iPSC-CM differentiation, characterization, and maturation is included. Both, current advances in the field and challenges yet to overcome emphasize the potential of using patient-derived cell models to mimic genetic cardiac diseases.

Repolarization instability and arrhythmia by IKr block in single human-induced pluripotent stem cell-derived cardiomyocytes and 2D monolayers

“…Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have created new perspectives in many fields, including developmental biology, drug testing, safety pharmacology, and disease modelling. 1 The implementation of cellular models for in vitro safety pharmacology has reduced drug attrition due to proarrhythmic effects. 2 Concurrently, the approval rate of new drugs fell, 3 indicating the need for more specific proarrhythmic tests and biomarkers.…”

Modeling Cardiac Disease Mechanisms Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Progress, Promises and Challenges

“…In LQTS2 iPSC-CM models, an increase of the action potential duration (APD) has been observed [ 144 ]. The phenotype has been recapitulated in vitro: an alteration of KCNH2 function, due to the presence of gene mutations, led to a decrease of the I Kr current and the development of arrythmias [ 145 ]. In 2013, Bellin et al, reported a mutation (N996I) in KCNH2 responsible for a moderate growth of the APD without early-after depolarization (EAD) [ 142 ].…”

Genome Editing for the Understanding and Treatment of Inherited Cardiomyopathies

“…This is particularly beneficial for therapies targeting the heart as patient-derived hiPSCs can easily be induced to differentiate into cardiomyocytes. These induced cardiomyocytes (iCMs) can then be used to explore the cardiac-specific effects of treatment on specific patient genetic backgrounds [60,61]. Advances in genome editing have revolutionized the cardiovascular field, allowing the creation of isogenic cell lines differing only at the locus of interest.…”