Date of Award

August 2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physics

Advisor(s)

M. Cristina Marchetti

Second Advisor

Teng Zhang

Keywords

active matter, Cell Mechanics, Collective cell migration, mechanochemical model, propagating waves, Soft matter

Subject Categories

Physical Sciences and Mathematics

Abstract

This dissertation investigates the physical mechanics of collective cell migration in monolayers of epithelial cells. Coordinated cell motion underlies a number of biological processes, including wound healing, morphogenesis and cancer metastasis, and is controlled by the interplay of single cell motility, cell-cell adhesions, cell-substrate interaction, and cell contractility modulated by the acto-myosin cytoskeleton. Here we examine the competing roles of these mechanisms via a continuum model of a tissue as an active elastic medium, where mechanical deformations are coupled to and feed back onto chemical signaling.

We begin in Chapter 1 with a brief review of cell migration at both the single-cell and many-cell levels, and of the experimental tools used to probe the mechanical properties of cells and tissues. In Chapter 2 we formulate our minimal continuum model of a tissue as an overdamped active elastic medium on a frictional substrate. The model couples mechanical deformations in the tissue to myosin-based contractile activity and to cell polarization. Two new ingredients of our model are: (i) a feedback between the on-off dynamics of myosin motors and the active contractile stresses they induce in the tissue, and (ii) the coupling of cell directed motion or polarization to tissue strain. In the following two chapters we employ this model to describe collective cell dynamics in expanding (Chapter 3) and confined (Chapter 4) tissues and compare with experiments. In expanding monolayers, as realized for instance in wound healing assays where an initially confined tissue is allowed to expand freely on a substrate, our model reproduces the propagating waves of mechanical stress observed in experiments and believed to play a key role in controlling the transmission of information across the tissue and mediating coordinated cell motion. Combining analytical and numerical work we construct a phase diagram that identifies various dynamical regimes in terms of single-cell properties, such as contractility and stiffness. In Chapter 4, we use our model to describe collective dynamics of cells confined to a circular geometry. In this case the propagating waves are replaced by standing sloshing waves guided by both contractility and polarization. The work on confined tissues was carried out in collaboration with the experimental group of Jeff Fredberg at the Harvard School of Public Health. By combining theory and experiment we can provide a quantitative understanding of how contractility and polarization regulate the mechanics of the tissue by renormalizing the tissue elastic moduli and controlling the frequency of oscillatory modes.

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Open Access

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