Hugh Xiao Dissertation Defense
Defense Abstract: Tissues and bodily fluids undergo continuous changes as a natural life cycle process. Extracellular matrices (ECMs), which provide structural and biochemical support for the cells, and extracellular fluids (ECFs), which transport nutrients, oxygen, and waste products, exhibit several mechanical properties that can impact cell behaviors. These properties include, for example, fibrillar alignment, density, and stiffness of ECMs, and osmolarity and viscosity of ECFs. These mechano-biological cues can impact cell behaviors and change tissue landscapes. Fibrosis is known for thickened extracellular matrix, which involves many changes in mechanical properties of extracellular environment. There is much to be explored as to how these mechanical changes can both be affected by and also regulate cellular behaviors in fibrotic progression.
In this thesis, I investgiate how mechanical properties of ECMs and ECFs affect liver and lung cells’ interactions with extracellular matrix, and conversely, how lung and liver cells induce these changes in a fibrotic progression. I choose liver and lung because they are commonly affected by fibrotic diseases. First, I present a computational pipeline which uses particle image velocimetry (PIV) to track cell-matrix interactions in biomimetic hydrogels. PIV measures not only the extent of fiber recruitment but also the speed. I applied this pipeline to study fiber recruitment by lung fibroblasts and assess the effects of various drug conditions on fiber recruitment. After understanding the baseline
remodeling events that can be induced by fibroblasts, my follow-up work dissect a novel tissue destruction phenomenon that we saw happen after tissue accumulation in our biomimetic gel. This tissue destruction is strikingly reminiscent of honeycombing, which describes air-filled voids in the lungs characteristic of several advanced-staged lung fibrotic diseases. I find that cell contraction and degradation drive the formation of these voids in our biomimetic hydrogels. Next, I present work on how cytoskeletal dynamics can impact how cells migrate and remodel ECM by liver cells. Specifically, I implement a multicellular tumor spheroid model of liver cancer cells to show how inhibition of cytoskeletal regulators can affect how liver cancer cells are able to remodel surrounding collagen and invade. Finally, I present work on how viscosity and osmolarity of ECFs can impact cell’s ability to contract collagen. I show that a temporary elevation in fluid viscosity can rapidly induce cells to densify collagen locally. Our data further show that microtubules, Rac1, Arp2/3, ROCK, and myosin are important regulators of viscosity-induced ECM remodeling. In addition, high osmotic pressures override viscosity-induced cell spreading by suppressesing membrane ruffling.
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