Maladaptive Cell Junction Remodeling in Arrhythmogenic Cardiomyopathy

Abstract

Cardiovascular disease has been, is, and will remain the leading cause of death worldwide. Currently, due to a lack of physiologically accurate preclinical cardiac models, research and development for cardiac disorders has been inefficient. Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) represent attractive alternatives to current preclinical models for their physiological relevance and accessibility in vitro. In this study, we aimed to characterize and identify the molecular mechanisms underlying Arrhythmogenic cardiomyopathy (ACM) using iPSC-CMs. ACM is an inherited cardiac disorder that causes life-threatening arrhythmias and myocardial dysfunction. Pathogenic variants in PKP2 (Plakophilin-2), a desmosome component within specialized cardiac cell junctions, cause the majority of ACM cases. However, the molecular mechanisms by which PKP2 variants induce disease phenotypes remain unclear. Here we built bioengineered platforms using genetically modified iPSC-CMs to model the early spatiotemporal process of cardiomyocyte junction assembly in vitro. Heterozygosity for truncating variant PKP2R413X reduced Wnt/β-catenin signaling, impaired myofibrillogenesis, delayed mechanical coupling, and reduced calcium wave velocity in engineered tissues. These abnormalities were ameliorated by SB216763, which activated Wnt/β-catenin signaling, improved cytoskeletal organization, and restored cell junction integrity in cell pairs, and improved calcium wave velocity in engineered tissues. Together, these findings highlight the therapeutic potential of modulating Wnt/β-catenin signaling in a human model of ACM.