Dissertation/Thesis Abstract

Signaling from matrix elasticity and TGF-β1 to cells of the cardiac valve
by Wang, Huan, Ph.D., University of Colorado at Boulder, 2013, 166; 3562064
Abstract (Summary)

Coordinated movement of cardiac valves controls unidirectional flow of the blood with every heart beat. Cardiac valves are composed of thin, pliable leaflets that withstand compressive tension, fluid shear stress, and bending stress as blood flows through them. The structure and the mechanical properties of the valves render them durable during the lifetime of human beings. However, changes in hemodynamic environment, inflammatory responses, and congenital valvular defects can all cause valves to undergo irreversible structural changes, one of which is calcific aortic stenosis (CAS). CAS affects 2-3% of the population over 65 years old in the western world, and the only effective treatment is valve replacement surgery. CAS is characterized by tissue stiffening and the formation of calcified nodules, the development of which is associated with abnormal differentiation of resident fibroblasts known as valvular interstitial cells (VICs). Upon tissue injury, VICs are activated to myofibroblasts which deposit excessive collagen and stiffen the matrix. Understanding how the pathogenic phenotype of VICs is regulated by cues from the matrix may lead to new therapeutic treatments for CAS. In this thesis, I examined how matrix elasticity and TGF-β1 regulate VIC phenotypes. First, I characterized the VIC population from porcine aortic valves and showed that this population is relatively homogeneous. When I cultured these primary cells on different substrates, I found that poly(ethylene glycol) hydrogels mimicked the native valve matrix better than tissue culture polystyrene plates with respect to preserving the quiescent fibroblast phenotype. At the level of signaling, I demonstrated that this is mediated through an elasticity-regulated PI3K/AKT pathway. Additionally, I showed that reduced matrix rigidity redirected activated valvular myofibroblasts into dormant fibroblasts without inducing significant apoptosis. Finally, I examined the effect of TGF-β1 on VIC gene expression over time with microarray-based gene expression profiling and found that TGF-β1 up-regulated cell-cell contact proteins (e.g., OB-cadherin, N-cadherin) in order to regulate valvular myofibroblast activation. Collectively, my thesis work revealed novel mechanosensing mechanisms employed by VICs to respond to matrix elasticity and explored the complex interactions among multiple extracellular cues, including matrix elasticity, TGF-β1 and cell-cell adhesion, to direct the cellular fate of VICs.

Indexing (document details)
Advisor: Leinwand, Leslie A., Anseth, Kristi S.
Commitee: Liu, Xuedong, Olwin, Bradley, Pace, Norm, Yi, Rui
School: University of Colorado at Boulder
Department: Molecular, Cellular and Developmental Biology
School Location: United States -- Colorado
Source: DAI-B 74/09(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Biology, Molecular biology, Cellular biology
Keywords: Cadherin, Hydrogel elasticity, Mechanosensing, Pi3k signaling, Tgf-beta1 signaling, Valvular myofibroblasts
Publication Number: 3562064
ISBN: 9781303094750
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