Inherited cardiac diseases, pluripotent stem cells, and genome editing combined—the past, present, and future

Abstract

Research on mechanisms underlying monogenic cardiac diseases such as primary arrhythmias and cardiomyopathies has until recently been hampered by inherent limitations of heterologous cell systems, where mutant genes are expressed in noncardiac cells, and physiological differences between humans and experimental animals. Human-induced pluripotent stem cells (hiPSCs) have proven to be a game changer by providing new opportunities for studying the disease in the specific cell type affected, namely the cardiomyocyte. hiPSCs are particularly valuable because not only can they be differentiated into unlimited numbers of these cells, but they also genetically match the individual from whom they were derived. The decade following their discovery showed the potential of hiPSCs for advancing our understanding of cardiovascular diseases, with key pathophysiological features of the patient being reflected in their corresponding hiPSC-derived cardiomyocytes (the past). Now, recent advances in genome editing for repairing or introducing genetic mutations efficiently have enabled the disease etiology and pathogenesis of a particular genotype to be investigated (the present). Finally, we are beginning to witness the promise of hiPSC in personalized therapies for individual patients, as well as their application in identifying genetic variants responsible for or modifying the disease phenotype (the future). In this review, we discuss how hiPSCs could contribute to improving the diagnosis, prognosis, and treatment of an individual with a suspected genetic cardiac disease, thereby developing better risk stratification and clinical management strategies for these potentially lethal but treatable disorders.

Myosin-18B Regulates Higher-Order Organization of the Cardiac Sarcomere through Thin Filament Cross-Linking and Thick Filament Dynamics

“…pathological cardiomyogenesis, which recapitulates key aspects of myofibrillogenesis (van den Brink et al, 2020;Kempf and Zweigerdt, 2018). Differentiation was followed over a 28-day period by immunofluorescence microscopy using NM2B, a-actinin-2, and bCM as markers of myofibril maturation (Figure 5A).…”

Using Cardiovascular Cells from Human Pluripotent Stem Cells for COVID-19 Research: Why the Heart Fails

“…However, with congenital LQTS occurring at a frequency of ∼1 in 2,000 individuals, it is clear that, given SARS-CoV-2 has infected >30 million people, LQTS patients are also requiring treatment. The numerous patient-derived hPSC disease models now available for genetic cardiac disorders ( van den Brink et al., 2019 ; Protze et al., 2019 ) provide a unique opportunity to determine rapidly which cardiac diseases and mutations are more sensitive to the use of these novel drugs. Such studies can be used in combination with SARS-CoV-2 infection and/or multiple drug treatments, modeling a clinical scenario where patients with variable genetic backgrounds undergo the same treatment.…”

Modeling Cardiovascular Diseases with hiPSC-Derived Cardiomyocytes in 2D and 3D Cultures

“…HiPS-CMs have also been used in electrophysiology studies based on patch clamp, calcium flux assays, and multielectrode arrays to describe aberrant features in genetic arrhythmic diseases, such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), sick sinus syndrome (SSS), as well as atrial fibrillation (AF) and Brugada syndrome (BrS) [33]. One of the first studies in which electrophysiological recording techniques have been used on hiPS-CMs was reported by Moretti at al., who found typical electrophysiological features of LQTS type 1 in patient-specific hiPS-CMs carrying a mutation in KCNQ1 gene, which encodes the alpha subunits of the channels responsible for I Ks generation [34].…”