Inherited cardiomyopathies are a set of pathological conditions that impact the structure and function of the heart. There are over 1,000 cardiomyopathy-causing mutations in genes encoding structural proteins in heart muscle cells, known as cardiomyocytes. The advents of human induced pluripotent stem cells (hiPSCs) and CRISPR/Cas9 technologies have opened a viable path for creating in vitro models to investigate therapeutic strategies for cardiac pathologies. However, hiPSC-derived cardiomyocytes (hiPSC-CMs) remain immature, limiting their capabilities to fully recapitulate disease phenotypes. Here, we report the variability in hiPSC-CM studies and discuss paths toward unification in hiPSC-CM model development, maturation, and assessment that we believe will drive progress in engineering mature cardiac tissue. We then utilized some of these models to investigate phenotypes of hypertrophic cardiomyopathy (HCM), showing that a beta-myosin heavy chain (MYH7) mutation leads to increased cell size, sarcomere content, contractility, mitochondria expression, and paracrine signaling of cardiomyocytes. While effects of HCM-causing mutations on cardiomyocyte function have been well-studied, it remains unclear how these mutations lead to a common HCM phenotype, fibrosis. Here, we used engineered cardiac microtissues (CMTs) comprised of MYH7-variant hiPSC-CMs and wild-type stromal cells, to dissect the multi-cellular interactions responsible for fibrosis. HCM-variant CMTs exhibited increased collagen deposition and tissue stiffening, resulting in a decrease in tissue contractility dependent on stromal cell proliferation. We show that this activation is paracrine driven through EGFR signaling and that EGF has synergistic effects with a well-known fibrosis mediator, TGF-β. Overall, our studies present a better understanding of how HCM-causing mutations impact cardiomyocyte function and how these changes impact stromal cell response leading to further disease progression. / 2024-08-29T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/46650 |
| Date | 30 August 2023 |
| Creators | Ewoldt, Jourdan K. |
| Contributors | Chen, Christopher S. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution 4.0 International, http://creativecommons.org/licenses/by/4.0/ |
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