Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Materials Science & Engineering

First Advisor

Vivek B. Shenoy

Abstract

To perform functions such as proliferation, differentiation, and locomotion, living cells establish stable attachments to the extracellular matrix (ECM) via the formation of specialized receptor mediated contact foci, through which they sense the mechanical stimuli from the ECM and adapt their cytoskeleton structures. The cellular contraction, on the other hand, may induce dramatic structural changes to the local extracellular environment, particularly for the fibrous matrices. The main goal of this thesis is to understand the cell-ECM interaction and cell-cell interaction, which lays the foundation to address the role of mechanical stimuli in several physiological and pathological processes such as cell differentiation, wound healing and tumor metastasis. First, we employ the shear-lag model to quantitatively identify the key parameters affecting the size of focal adhesions, which physically link the cytoskeleton to the ECM and serve as the signal hubs. Next, by extending the SLM to three-dimensional and including the fibrous nature of ECM, we study the cell mechanosensing in non-linear ECMs. Furthermore, we focus on the whole-cell level and study nuclear morphology and stress during tumor cell transmigration. Notably, our model explains the driving force for tumor cell transmigration and shows potential treatment by preventing cancer cell extravasation. The nuclear morphology and stress predicted by the model lay the foundation to study the anticipated extent of DNA damage during transmigration. Finally, we study the gap formations due to the failure of cell-cell adhesions in endothelium and show that the adaptive cellular contraction plays a crucial role in preventing gap development and preserving the barrier function.

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