Modeling Development and Disease In Human Engineered Cardiac TissueRupert, Cassady ElisecreatorCoulombe, KareenAdvisorBlack, LaurenReaderColvin, VickiReaderHurt, RobertReaderMathiowitz, EdithReaderMende, UlrikeReaderBrown University. Biology and Medicine: Biomedical Engineeringsponsor2019xii, 184 p.born digitalThesis (Ph. D.)--Brown University, 2019thesesCardiovascular engineering using human pluripotent stem cell (hPSC)-derived cardiomyocytes holds incredible potential for disease modeling, therapeutic development and testing, and cardiac regeneration. The heterogeneity and plasticity of hPSCs and hPSC-cardiomyocytes can be both assets and obstacles to the generation and advancement of new technologies, and a deeper understanding of how to manipulate these cells is needed. The research pursued in this dissertation explores novel means to engineer healthy and diseased states in hPSC-cardiomyocytes from the single-cell to tissue level. Studies were performed using a broad scale of metrics including cell and tissue structure, gene expression, bioenergetic phenotype, and electromechanical function in order to obtain a fuller picture of hPSC-cardiomyocyte response to mechanical, biochemical, and cellular stimuli. Important and novel findings show that (1) confocal microscopy imaging of single cells reveals hPSC-cardiomyocyte contractile lattice and cytosolic volume respond independently to hypertrophic stimulation; (2) developmental growth factors stimulate proliferation and metabolic maturation of hPSC-cardiomyocytes in engineered tissues; (3) adult human cardiac fibroblasts can be manipulated to produce physiological and pathophysiological phenotypes in engineered tissues; and (4) metabolic selection to purify hPSC-cardiomyocyte populations changes bioenergetic phenotype. Taken together, these results stress the importance of considering hPSC-cardiomyocyte immaturity and plasticity in engineered cardiac tissues, and that, because of these features, hPSC-cardiomyocytes provide unexpected avenues for engineering development and disease in the dish.tissue engineeringinduced pluripotent stem cellsEmbryonic stem cells--ResearchHeart cellsEnglishRPB20200720In CopyrightCollection is open for research.dissertations