Hsieh, Jeanne2025-01-282025-01-282024-08https://hdl.handle.net/11299/269661University of Minnesota Ph.D. dissertation. August 2024. Major: Biomedical Engineering. Advisor: Brenda Ogle. 1 computer file (PDF); ix, 147 pages.Heart disease is the leading cause of death worldwide. To discover potential therapeutic strategies, human in vitro model systems are under development. Cardiac monolayers, which contain only cardiomyocyte populations, allow for the study of disease-associated molecular and cellular alterations specific to cardiomyocytes. Engineered heart tissue (EHT) models which contain multiple cardiac cell types, allow direct measurement of tissue scale contractile force, enable the investigation of cardiac functional changes due to pathological intercellular communication, and are typically more mature than cardiac monolayers because of passive mechanical loading with culture. In the first part of my thesis, I investigated the cellular and molecular hallmarks of hypertrophic cardiomyopathy (HCM) using cardiac monolayers. In the second part of my thesis, I studied the interplay of cardiomyocytes and fibroblasts using EHTs. Both models relied on the generation of human induced pluripotent stem cells (hiPSCs) with mutations in the myosin heavy chain (MHC) converter domain, namely the homozygous MYH7 c.2167C > T (R723C) mutation and the heterozygous MYH6 c.2173C > T (R725C) mutation both associated with HCM. In the 2D study, extracellular matrix (ECM) dynamics were newly identified as an early-stage characteristic of disease pathogenesis. In the second part of my thesis, a 3D EHT model was developed that included fibroblasts, support cells and primary ECM producers of the heart. I found that early-stage, pathological ECM dynamics in mutant hiPSC-derived cardiomyocytes (hiPSC-CMs) were mediated via the expression of TGF-beta1 by cardiomyocytes. Overall, these findings provide a promising foundation for developing and implementing novel strategies to treat HCM well before the manifestation of clinically detectable cardiac dysfunction.enEngineered heart tissueExtracellular matrixHuman induced pluripotent stem cell-derived cardiomyocytesHypertrophic cardiomyopathyMyosin heavy chain mutationsTransforming growth factor beta-1Thesis or Dissertation