Hypertrophic cardiomyopathy–associated mutations drive stromal activation via EGFR-mediated paracrine signaling
Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the left ventricular wall, diastolic dysfunction, and fibrosis, and is associated with mutations in genes encoding sarcomere proteins. While in vitro studies have used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to study HCM, these models have not examined the multicellular interactions involved in fibrosis. Using engineered cardiac microtissues (CMTs) composed of HCM-causing <i>MYH7</i>-variant hiPSC-CMs and wild-type fibroblasts, we observed cell-cell cross-talk leading to increased collagen deposition, tissue stiffening, and decreased contractility dependent on fibroblast proliferation. hiPSC-CM conditioned media and single-nucleus RNA sequencing data suggested that fibroblast proliferation is mediated by paracrine signals from <i>MYH7</i>-variant cardiomyocytes. Furthermore, inhibiting epidermal growth factor receptor tyrosine kinase with erlotinib hydrochloride attenuated stromal activation. Last, HCM-causing <i>MYBPC3</i>-variant CMTs also demonstrated increased stromal activation and reduced contractility, but with distinct characteristics. Together, these findings establish a paracrine-mediated cross-talk potentially responsible for fibrotic changes observed in HCM.
Authors
- Joshua Gorham (ORCID: https://orcid.org/0000-0001-5969-4690)
- Christine E. Seidman (ORCID: https://orcid.org/0000-0001-6380-1209)
- Jonathan G. Seidman (ORCID: https://orcid.org/0000-0002-9082-3566)
- Linqing Li (ORCID: https://orcid.org/0000-0003-3003-9902)
- Paige E. Cloonan (ORCID: https://orcid.org/0000-0003-1031-281X)
- Anant Chopra
- Rebeccah J. Luu (ORCID: https://orcid.org/0000-0003-4364-8985)
- Jourdan K. Ewoldt (ORCID: https://orcid.org/0000-0001-5466-8557)
- Micheal A. McLellan (ORCID: https://orcid.org/0000-0003-1946-5038)
- Jon A. L. Willcox (ORCID: https://orcid.org/0000-0002-3782-4770)
- Christopher N. Toepfer (ORCID: https://orcid.org/0000-0003-4671-2030)
- Jeroen Eyckmans (ORCID: https://orcid.org/0000-0003-1475-8149)
- Daniel M. DeLaughter (ORCID: https://orcid.org/0000-0002-5352-2502)
- Christopher S. Chen (ORCID: https://orcid.org/0000-0003-2445-8449)
- Josh Lee (ORCID: https://orcid.org/0009-0004-7699-4555)
- Miranda C. Wang (ORCID: https://orcid.org/0000-0002-9534-5276)
- Xining Gao (ORCID: https://orcid.org/0009-0007-1105-4943)
- Olivia Layton
Institutions
- Boston University (US)
- Brigham and Women's Hospital (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- University of New Hampshire (US)
- University of Oxford (GB)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1126/sciadv.adi6927
- Citations
- 9
- Primary Topic
- Cardiomyopathy and Myosin Studies
- Type
- article
- Field-Weighted Citation Impact
- 3.62
Funders
- Fondation Leducq