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Published on: November 3, 2020
Spatiotemporal cell junction assembly in human iPSC-CM models of arrhythmogenic cardiomyopathy
Sean L Kim1, Michael A Trembley2, Keel Yong Lee3
1Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA 02134, USA; Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA.
Insights
Genetic defects in Plakophilin-2 (PKP2) cause arrhythmogenic cardiomyopathy (ACM). Modulating Wnt/β-catenin signaling in human heart cells shows promise for treating this inherited cardiac disorder.
Area of Science:
- Cardiovascular Research
- Genetics
- Cell Biology
Background:
- Arrhythmogenic cardiomyopathy (ACM) is an inherited heart condition leading to arrhythmias and dysfunction.
- Most ACM cases stem from pathogenic variants in Plakophilin-2 (PKP2), a key desmosome protein.
- The precise molecular mechanisms linking PKP2 variants to ACM phenotypes are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying PKP2-associated ACM using a human stem cell model.
- To explore the role of Wnt/β-catenin signaling in cardiomyocyte junction assembly and function in ACM.
Main Methods:
- Development of bioengineered platforms using genetically modified human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
- Modeling of cardiomyocyte junction assembly in vitro.
- Assessment of Wnt/β-catenin signaling, myofibrillogenesis, mechanical coupling, and calcium wave velocity in engineered tissues with a PKP2 variant (PKP2R413X).
- Evaluation of therapeutic effects of SB216763, a Wnt/β-catenin signaling activator.
Main Results:
- Heterozygous PKP2R413X variant reduced Wnt/β-catenin signaling, impaired myofibrillogenesis, delayed mechanical coupling, and decreased calcium wave velocity in hiPSC-CM engineered tissues.
- SB216763 treatment ameliorated these abnormalities by activating Wnt/β-catenin signaling, improving cytoskeletal organization and cell junction integrity, and enhancing calcium wave velocity.
Conclusions:
- PKP2 variants disrupt cardiomyocyte junction assembly and function through altered Wnt/β-catenin signaling.
- Modulating Wnt/β-catenin signaling represents a potential therapeutic strategy for ACM.
- This study provides a human cell-based model for investigating ACM pathogenesis and therapeutic interventions.
Abstract:
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/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, 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.
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