Advanced tool and methods for modeling cardiovascular disease using human pluripotent stem cells

Abstract

To advance drug discovery for cardiovascular patients, new pre-clinical models and quantification methods are needed to improve clinical predictivity. This thesis aims to explore several approaches to bringing new solutions for disease modeling which reflect the human heart. Firstly, we review the current status of the Heart-on-chip (HoC) field and the cutting edge (bio)materials which enable more physiologically relevant culture methods for stem cell-derived cardiomyocytes (hiPSC-CMs). Then, we use a polydimethylsiloxane chip to culture hiPSC-CM, hiPSC-endothelial cells and hiPSC-cardiac fibroblasts combined with a microfluidic flow-channel to mimic physiological blood flow. Subsequently, we fabricated and tested a platform for 3D-culture of heart tissues designed ultimately for medium- to high-throughput drug screening. Moreover, we create a stand-alone software application for automated and robust analysis of in vitro models of striated muscle. We have used a previously published mathematical tool and applied it to static, live, 2D, 3D, hiPSC-CM, primary CM and skeletal muscle, providing evidence of its versatility. This was successfully applied to study hiPSC-CMs from patients with hypertrophic cardiomyopathy and carrying a heterozygous mutation in the MYBPC3 gene. Finally, we discuss the results and conclusions presented in this thesis, and provide an outlook of future research directions in this exciting field.