Spatiotemporal cell junction assembly in human iPSC-CM models of arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that causes life-threatening arrhythmias and myocardial dysfunction. Pathogenic variants in Plakophilin-2 (PKP2), 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 human induced pluripotent stem cell-derived cardiomyocytes to model the early spatiotemporal process of cardiomyocyte junction assembly in vitro. Heterozygosity for truncating variant PKP2R413X reduced Wnt/ß-catenin signaling, impaired myofibrillogenesis, delayed mechanical coupling, and reduced calcium wave velocity in engineered tissues. These abnormalities were ameliorated by SB216763, which activated Wnt/ß-catenin signaling, improved cytoskeletal organization, 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/ß-catenin signaling in a human model of ACM.

Cellular and Molecular Mechanism of Cardiac Regeneration: A Comparison of Newts, Zebrafish, and Mammals.

Cardiovascular disease is the leading cause of death worldwide. Current palliative treatments can slow the progression of heart failure, but ultimately, the only curative treatment for end-stage heart failure is heart transplantation, which is only available for a minority of patients due to lack of donors' hearts. Explorative research has shown the replacement of the damaged and lost myocardium by inducing cardiac regeneration from preexisting myocardial cells. Lower vertebrates, such as the newt and zebrafish, can regenerate lost myocardium through cardiomyocyte proliferation. The preexisting adult cardiomyocytes replace the lost cells through subsequent dedifferentiation, proliferation, migration, and re-differentiation. Similarly, neonatal mice show complete cardiac regeneration post-injury; however, this regenerative capacity is remarkably diminished one week after birth. In contrast, the adult mammalian heart presents a fibrotic rather than a regenerative response and only shows signs of partial pathological cardiomyocyte dedifferentiation after injury. In this review, we explore the cellular and molecular responses to myocardial insults in different adult species to give insights for future interventional directions by which one can promote or activate cardiac regeneration in mammals.