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Open Access Dissertation
Doctor of Philosophy (PhD)
Year Degree Awarded
Month Degree Awarded
Biochemical and Biomolecular Engineering | Biological Factors | Biology and Biomimetic Materials | Biomaterials | Cancer Biology | Cardiovascular Diseases | Cardiovascular System | Cell Biology | Mechanics of Materials | Molecular, Cellular, and Tissue Engineering | Neoplasms | Polymer and Organic Materials | Polymer Science | Tissues
The goal of this dissertation was to parse the roles of physical, mechanical and chemical cues in the phenotype plasticity of smooth muscle cells (SMCs) in atherosclerosis. We first developed and characterized a novel synthetic hydrogel with desirable traits for studying mechanotransduction in vitro. This hydrogel, PEG-PC, is a co-polymer of poly(ethylene glycol) and phosphorylcholine with an incredible range of Young’s moduli (~1 kPa - 9 MPa) that enables reproduction of nearly any tissue stiffness, exceptional optical and anti-fouling properties, and support for covalent attachment of extracellular matrix (ECM) proteins. To our knowledge, this combination of mechanical range, low price, and ease-of-use is unmatched by any other hydrogel. We further used PEG-PC to evaluate the impact of substrate stiffness on the proliferation and adhesion properties of three cancer cell lines in 2D, from which we conclude that mechanotransduction is cell type-dependent and differences in focal adhesion-mediated signaling affect proliferation outcomes.
With PEG-PC as a substrate, we then designed a complex in vitro model to recapitulate characteristic changes in the surrounding microenvironment that SMCs experience during the progression of atherosclerosis. These changes include the composition of the ECM, the availability of soluble factors, and the surrounding mechanical environment. Our findings point to ECM composition as the primary regulator of SMC behaviors and characteristics, in part by modulating the effects of soluble factors. Unexpectedly, changes in substrate stiffness had a relatively modest effect. In spite of large ECM-directed differences in proliferation and motility, we did not find that these behaviors are inversely related to SMC marker expression, nor was marker expression substantially dependent on ECM composition despite being regulated by focal adhesion kinase signaling. Finally, our findings suggest that the transition from a migratory to a proliferative phenotype in atherosclerosis is mediated by the changing ECM composition, and we propose hypothetical, integrin-driven models to explain this switch. From these conclusions, we emphasize the importance of increasing the complexity of in vitro models to carefully match critical features of the in vivo microenvironments. We expect this approach to produce physiologically relevant behaviors, and in doing so we may identify novel, context-dependent therapeutic targets.
Herrick, William G., "Mimicking the Arterial Microenvironment with PEG-PC to Investigate the Roles of Physicochemical Stimuli in SMC Phenotype and Behavior" (2015). Doctoral Dissertations. 367.
Biochemical and Biomolecular Engineering Commons, Biological Factors Commons, Biology and Biomimetic Materials Commons, Biomaterials Commons, Cancer Biology Commons, Cardiovascular Diseases Commons, Cardiovascular System Commons, Cell Biology Commons, Mechanics of Materials Commons, Molecular, Cellular, and Tissue Engineering Commons, Neoplasms Commons, Polymer and Organic Materials Commons, Polymer Science Commons, Tissues Commons