Abstract

Interactions between cells and the extracellular matrix (ECM) are important for fundamental cellular processes, including migration, proliferation, and differentiation. The influence of ECM mechanical properties and local fiber network architecture on cell behavior has been extensively studied using elastic hydrogels and collagen-I matrices. Recent works have demonstrated that cells can sense distant matrix layers without direct contact — for example, a single cancerous cell can mechanosense a stiff basal surface across a depth of 10 μm. Cell collectives progressively deform collagen fiber networks, altering ECM mechanical properties beyond single-cell dimensions, and these local structural and mechanical changes in turn further modulate cellular response. This dissertation investigates the roles of fibrous collagen matrix in the collective depth sensing and mechanical memory of epithelial cells. Chapter 2 examines whether cellular collectives can perform “depth-mechanosensing” through thick fibrous matrices. Using a collagen–polyacrylamide double-layer hydrogel to measure cell clustering and collagen deformation, we show that epithelial cell collectives may mechanosense basal substrates at depths exceeding 100 μm. On stiffer basal substrates, cells initially migrate more slowly while driving greater collagen deformation and stiffening, resulting in reduced dispersion of epithelial clusters. We demonstrate that this depth-mechanosensing in epithelial cell clusters can be disrupted by myosin-II inhibition or by α-catenin depletion. Together, these results suggest that depth-mechanosensing is an emergent property arising from collective collagen deformation driven by epithelial cell clusters, offering insights into tissue contexts with layers of different stiffness, including tumor invasion and wound healing. Chapter 3 investigates the role of the native fibrous ECM in cellular mechanical memory. We demonstrate that cells can encode mechano-memory in primed collagen matrices, which subsequently alter future epithelial cell migration. Epithelial cells seeded on primed matrices exhibit enhanced migration velocities and modified trajectories, driven by remodeling-induced changes in collagen structure — including heterogeneous fiber distribution and fiber alignment — as well as altered mechanical properties. Environmental perturbations such as hypoxia and lysyl oxidase (LOX) inhibition modify collagen properties and reduce the migration velocity of subsequently seeded cells. Taken together, these findings show that both the structural and mechanical properties of collagen matrices shape the mechano-memory encoded within them, with important implications for therapies targeting pathologies driven by spatiotemporal changes in cell and tissue mechanics, including cancer metastasis and fibrogenesis.

Committee Chair

Amit Pathak

Committee Members

Gretchen Meyer; Jianjun Guan; Philip Bayly; Spencer Lake

Degree

Doctor of Philosophy (PhD)

Author's Department

Mechanical Engineering & Materials Science

Author's School

McKelvey School of Engineering

Document Type

Dissertation

Date of Award

7-23-2026

Language

English (en)

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Available for download on Saturday, July 22, 2028

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