| Worldwide increases in life expectancy have been paralleled by a greater prevalence of chronic and age-associated disorders, particularly of the cardiovascular system. Advances in regenerative medicine have propelled novel cellular platforms for disease modeling and rejuvenation strategies. Bioengineered induced pluripotent stem cells (iPSCs) represent a promising platform for disease modeling, drug testing, and therapeutic applications. Chapter I reviews the recent progress of cardiac disease modeling using bioengineered stem cells and highlights the limitations of this technology. Chapter II documents the materials and methods used throughout this thesis. Chapter III describes the development of a quality control assay to purge residual teratoma-forming progenitors prior to cardiac regeneration. This key finding eliminates the inherent risk of teratogenicity and promotes next-generation bioengineered stem cell-based reparative therapy. Chapter IV demonstrates the capacity of iPSC-derived cardiomyocytes to model structural and functional deficiencies of RBM20 familial dilated cardiomyopathy (DCM). Using this platform, Chapter V investigates stage-specific transcriptome profiling of RBM20 familial DCM and identifies novel molecular perturbations during early stages of cardiogenesis. Chapter VI characterizes in vitro susceptibility to beta-adrenergic stress and pharmacologically modulates disease-relevant stress responses using Ca2+ channel blocker, verapamil and beta-blocker, carvedilol. Chapter VII summarizes the main findings in this thesis work and provides a novel model of iPSC-based disease discovery to predict patient-specific susceptibility to stress and injury. Chapter VIII highlights a novel educational initiative for medical students launched by Saranya Wyles concurrently with this thesis work. |
