Mechanobiological Analysis Of The Developing Atrioventricular Valve
Valvular structural and functional defects account for millions of defects in human births, and their effects can be immediately life threatening or cause more subtle cell and/or matrix changes that can lead to functional defects later in life. Nearly all study of mechanical action on cellular function focuses on the "normal and pathological" adult age. This neglects key stages in the functional life cycle of tissues where remodeling is most active yet, controlled, early development. Until the basic interactions between cells and their microenvironment are understood in this context, our ability to understand congenital malformation and manipulate these phenomena remains limited. The objective of this thesis was to understand the role of mechanics combined with biology during the developmental process of valvulogenesis. This thesis demonstrates that valve interstitial cells respond to mechanical strain and directionality by regulating cellular proliferation, differentiation, and matrix remodeling. Using a novel bioreactor and in-vivo perturbation studies, we found that mechanical stretch directly inhibits myofibroblastic activation in mitral valve progenitor cells through a RhoA dependent mechanism. Consequently, Rac1 expression is promoted matrix condensation, as typically seen in mature quiescent leaflets. In post-natal valve maturation, we determined that tissue stretch correlates with tissue biomechanics and underlying cellular deformation. However, in pathological conditions such as Marfan Syndrome, tissue stretch becomes decoupled with cellular deformation by an unknown mechanism. Lastly, we modeled the molecular mechanisms of early cushion development applying systems biology model of ordinary differential equations. In addition to predicting and confirming a new heterogeneous phenotype, we concluded with 3 other possible hypotheses, which are included in the discussion. The biological and computer models developed in this thesis can be used in future experiments to explore the combined biological and mechanical regulation of multi-scale valve formation. My hope is that the results presented in this thesis will eventually be useful for developing efficient strategies to control tissue adaptation and remodeling as well as accelerate the construction of cardiovascular tissue replacements.
Valvulogenesis; Mechanics; Biology
Butcher, Jonathan T.
Varner, Jeffrey D.; Evans, Todd
Ph. D., Biomedical Engineering
Doctor of Philosophy
dissertation or thesis