MECHANOBIOLOGICAL REGULATION OF ATRIOVENTRICULAR VALVE MORPHOGENESIS
Around 1% of live births have a congenital heart defect (CHD), a majority of which include defects in the structure and function of heart valves. Pediatric patients face years of surgical interventions and treatments because current replacement valves cannot grow with the heart throughout postnatal development. Genetic causes for CHDs are insufficient to explain the prevalence, variety and concurrent combinations of these defects. Heart valve development progresses in a tightly controlled, time dependent manner, in an intensifying hemodynamic environment. The fact that hemodynamic forces, including flow induced deformations and shear stresses, affect valve development has been well established. Yet, little is still known on how hemodynamic stresses interact with prescribed ligand signaling programs to orchestrate cellular activities that bring about valve morphogenesis. The objective of this thesis was to elucidate the influence of mechanical stress on the biology of valve embryonic cells to determine how mechanical stimuli regulate normal development and act as epigenetic causes of congenital disease. Using an osmotic stress method novel to valve developmental studies, we have identified unique roles for tensile and compressive stresses in directing valve remodeling and sizing through changes in proliferation and cell contractility. Using in silico systems biology methods and in vitro bioreactor data, this work also elucidated on the roles of shear stress on regulating endothelial to mesenchymal transition in valve development. Additionally, this work contributed to the understanding of epithelial to mesenchymal driven metastasis by uncovering the signaling by which cells make decisions and acquire a collective, migratory phenotype. Overall, it is hoped that the findings and tool development set forth in this work will contribute to improving clinical outcomes for patients with congenital defects and in need of regenerative tissue engineered solutions.
Computational modeling; Congenital heart defects; Heart valve development; Mechanobiology; Osmotic stress; Systems biology
Butcher, Jonathan T.Varner, Jeffrey D.
Lammerding, Jan; Cosgrove, Benjamin D.
Ph. D., Biomedical Engineering
Doctor of Philosophy
dissertation or thesis