Modelling arrhythmogenic cardiomyopathy fattyfibro pathology with PKP2-deficient epicardial cells derived from human iPSCs
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.
Authors
- Jessika Iwanski (ORCID: https://orcid.org/0000-0003-2482-5376)
- Sailu Sarvagalla (ORCID: https://orcid.org/0000-0001-7428-7663)
- Talal Moukabary (ORCID: https://orcid.org/0000-0001-6557-6404)
- Elizabeth Juneman (ORCID: https://orcid.org/0000-0003-1771-562X)
- Sobhi G. Kazmouz
- Jared M. Churko (ORCID: https://orcid.org/0000-0003-3537-9834)
- Rebekah L. Gundry (ORCID: https://orcid.org/0000-0002-9263-833X)
- Zachary Laksman (ORCID: https://orcid.org/0000-0002-7790-541X)
- Ning Ma (ORCID: https://orcid.org/0000-0002-1775-2992)
- Cynthia A. James (ORCID: https://orcid.org/0000-0001-8040-4600)
- Paul Hanson (ORCID: https://orcid.org/0000-0002-0655-4843)
- Burcu Baş
- Leili Rohani (ORCID: https://orcid.org/0009-0004-5185-6789)
- Sadia L. Falana
- Hugh Calkin
Institutions
- University of Arizona (US)
- University of British Columbia (CA)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Southwestern Medical Center (US)
- Southwestern Medical Center (US)
- University of Nebraska Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-10-27
- DOI
- https://doi.org/10.1038/s42003-025-08921-z
- Primary Topic
- Cardiovascular Effects of Exercise
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Johns Hopkins University
- National Heart, Lung, and Blood Institute