Elucidating Mechanosensitive Pathways in Cardiogenesis Through Combined Experimental and Numerical Approaches

Congenital heart defects (CHDs) are the leading cause of birth-defect infant mortality worldwide and occur in approximately 1% of live births. Despite their prevalence, the etiologies of many CHDs are still unknown. It’s been established that blood flow dynamics, or hemodynamics, act through mechanosensitive pathways to regulate cardiogenesis. Experimental models such as embryonic chicks serve as appropriate tools to perturb the hemodynamic environment to understand how hemodynamics regulate heart development. Specifically, these studies have found that the developing heart is particularly sensitive to hemodynamic forces such as wall shear stress (WSS). Unfortunately, measuring WSS in vivo at high resolution is unfeasible due to the small size and constant motion of the embryonic heart in model systems such as the embryonic chick. An alternative to the direct measurement approach is using numerical methods to simulate blood flow in the embryonic heart, such as computational fluid dynamics (CFD) and fluid-structure integration (FSI) models. In this thesis we use computational methods to elucidate the embryonic chick heart hemodynamic and biomechanical environment. We develop a CFD model of rigid vessels at the outlet of the early heart that is sensitive to blood flow and prone to defects. I inform the fluid domain of this model using high-resolution light sheet fluorescence microscopy (LSFM) imaging of cohorts of chicks using a pipeline we develop. We then apply this pipeline to perform parallel in ovo and in silico blood viscosity perturbations to examine how altered WSS impacts heart development. Additionally, we describe a preliminary FSI model based on the immersed boundary (IB) method to capture the biomechanical environment conducive for efficient valveless pumping for generating unidirectional blood flow. In total, this work provides tools that can be modified and expanded to explore mechanosensitive pathways related to hemodynamics in heart development.