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<p>Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease marked by progressive fattyfibro replacement of the ventricular myocardium, life-threatening arrhythmias, and sudden cardiac death. To dissect epicardial contributions to ACM pathogenesis, we generated iPSC lines from patients carrying plakophilin 2 (PKP2) 1849C &gt; T or PKP2 2013delC mutations, their CRISPR/Cas9–corrected isogenic controls, and a PKP2 knockout line. Epicardial cells (hPSC-EPCs) differentiated from mutant and knockout backgrounds exhibit enhanced epithelial-to-mesenchymal transition characteristics, increased lipid accumulation, and a pronounced fibrotic phenotype. RNA-seq performed on ACM hPSC-EPCs reveals dysregulation of Wnt, interferon, and Rho GTPase signaling, including an upregulation of insulin growth factor 2 (IGF2) and a key adipogenic transcription factor, <i>CEBPA</i>. Subsequent treatment of control and PKP2KO hPSC-EPCs with recombinant IGF2 enhances <i>CEBPA</i> expression, suggesting that insulin growth factor signaling contributes to ACM fattyfibro remodeling.</p>

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Modelling arrhythmogenic cardiomyopathy fattyfibro pathology with PKP2-deficient epicardial cells derived from human iPSCs

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Sadia L. Falana,
  • Sobhi G. Kazmouz,
  • Jessika B. Iwanski,
  • Sailu Sarvagalla,
  • Blaire E. Bas,
  • Elizabeth Juneman,
  • Talal Moukabary,
  • Ning Ma,
  • Rebekah L. Gundry,
  • Leili Rohani,
  • Paul Hanson,
  • Zachary Laksman,
  • Cynthia A. James,
  • Hugh Calkin,
  • Jared M. Churko

摘要

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease marked by progressive fattyfibro replacement of the ventricular myocardium, life-threatening arrhythmias, and sudden cardiac death. To dissect epicardial contributions to ACM pathogenesis, we generated iPSC lines from patients carrying plakophilin 2 (PKP2) 1849C > T or PKP2 2013delC mutations, their CRISPR/Cas9–corrected isogenic controls, and a PKP2 knockout line. Epicardial cells (hPSC-EPCs) differentiated from mutant and knockout backgrounds exhibit enhanced epithelial-to-mesenchymal transition characteristics, increased lipid accumulation, and a pronounced fibrotic phenotype. RNA-seq performed on ACM hPSC-EPCs reveals dysregulation of Wnt, interferon, and Rho GTPase signaling, including an upregulation of insulin growth factor 2 (IGF2) and a key adipogenic transcription factor, CEBPA. Subsequent treatment of control and PKP2KO hPSC-EPCs with recombinant IGF2 enhances CEBPA expression, suggesting that insulin growth factor signaling contributes to ACM fattyfibro remodeling.