Embryonic Mechanics

Thrust 1: Biomechanical Regulation of Valvulogenesis

Heart valves initiate as specific regions of endocardium within the atrioventricular canal and outflow tract of the heart tube that undergo an endocardial to mesenchymal transformation (EMT), forming valvuloseptal primordia called cushions. The molecular regulation of cushion formation is well studied; however defects in these early events are not survivable. Much less is known about the events regulating Post-EMT cushion remodeling into valves. This involves three simultaneous processes: (1) elongation and condensation of the tissue into thin leaflets or cusps, (2) mesenchymal differentiation to a fibroblastic phenotype, and (3) acquisition of a stratified extracellular matrix (ECM) architecture. Defects in these later remodeling events are of strong clinical concern because they are survivable but immediately life threatening or predispose the valve to premature structural failure. While regulatory molecules have been identified, including ligands (e.g. TGF-β, BMP, VEGF, Jag/Dll, Wnt, EGF) and their receptors, transcription factors (e.g. smads, snail/slug, Notch, Tbx5, Twist1, Tbx20, Sox9, Scleraxis, NFATc1, β-catenin), and matricellular proteins (e.g., hyaluronic acid, versican, periostin), the important coordination of these pathways remain unclear. Genetic deletion of many of these individual genes result in similar malformation outcomes that are mechanically insufficient. Hemodynamic maldistribution has been postulated as a causal mechanism of clinical CHD, but before our work was almost always studied as a consequence of genetic/biological perturbations rather than the other way around. We test novel hypotheses that these molecular interactions underlie coordinated cellular decisions in response to their hemodynamic environment to correctly elongate and remodel the valvuloseptal apparatus. Elucidation of these multi-scale bio-engineering programs is a critical need for bio-inspired intervention strategies to improve morphological and functional outcomes. 

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