Epicardial differentiation drives fibro-fatty remodeling in arrhythmogenic cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Stem Cell Biology
• Molecular Cardiology

Background:

• Arrhythmogenic cardiomyopathy (ACM) is an inherited heart condition characterized by fibro-fatty tissue accumulation.
• The cellular origins and molecular mechanisms driving ACM's fibrotic remodeling remain incompletely understood.
• Limitations in existing animal models hinder the study of ACM pathogenesis.

Purpose of the Study:

• To investigate the contribution of epicardial cells to fibro-fatty remodeling in arrhythmogenic cardiomyopathy.
• To identify the molecular mechanisms underlying epicardial changes in ACM.
• To explore potential therapeutic targets for ACM.

Main Methods:

• Utilized human-induced pluripotent stem cell (hiPSC)-derived cardiac cultures and epicardial cells from ACM patients and healthy donors.
• Employed single-cell RNA sequencing (scRNA-seq) to analyze cellular changes and gene expression.
• Conducted siRNA-mediated gene targeting and gain/loss-of-function studies on epicardial cells.
• Examined explanted human ACM hearts for epicardial activation and specific gene expression.

Main Results:

• hiPSC-derived epicardial cells from ACM patients exhibited spontaneous fibro-fatty differentiation.
• Targeting desmosomal genes in healthy hiPSC-epicardial cells mimicked ACM-related changes.
• scRNA-seq identified TFAP2A (activating enhancer-binding protein 2 alpha) as a key regulator of this process.
• TFAP2A promotes epicardial differentiation via enhanced epithelial-to-mesenchymal transition (EMT).
• TFAP2A expression and epicardial activation were observed in explanted ACM hearts.

Conclusions:

• TFAP2A-mediated epicardial EMT is a critical mechanism driving fibro-fatty remodeling in arrhythmogenic cardiomyopathy.
• Epicardial cells play a significant role in the pathogenesis of ACM.
• Targeting TFAP2A and the EMT pathway presents a potential therapeutic strategy for ACM.