2022 Theses Doctoral

Cardiomyopathy at the Intersection of Stem Cells and Tissue Engineering

Wang, Bryan Zicheng

Advances in genome editing, human induced pluripotent stem cells (iPSC), and cardiac tissue engineering have significantly improved the ability of in vitro models to model cardiac disease. The objective of this dissertation is to leverage cardiac tissue engineering to generate meaningful biological insights into human genetic cardiomyopathies. First, we studied a novel, de novo mutation in the filamin C (FLNC) gene which causes restrictive cardiomyopathy in a young patient. Using engineered cardiac tissues, we showed that this mutation causes a restrictive phenotype marked by increased passive tension and slowed contraction velocities.

Complementing our engineered tissues, we used high-throughput calcium imaging to identify compounds which improved myocardial relaxation in mutant cardiomyocytes. These compounds improved function of mutant cardiac tissues, suggesting a potentially targetable pathway in the patient’s mutation. In another study, engineered cardiac tissues and stem cells were used to study BAG3, a dilated cardiomyopathy- related gene, in cardiac fibroblasts. BAG3-/- and wild-type iPSCs were differentiated to cardiac fibroblasts and cardiomyocytes. By generating fully isogenic cardiac tissues and altering cellular genotypes, we determined that the loss of BAG3 in cardiac fibroblasts was deleterious to cardiac tissue function despite genetically normal cardiomyocytes. Further work studying cardiac fibroblasts revealed a mechanistic function of BAG3 in regulating cardiac fibroblast extracellular matrix synthesis. Together, this work highlights the ability of cardiac tissues and stem cells to unravel the complexities of genetic heart disease.