Analysis and Modeling of the Dynamics of Traction Forces during Cell Polarization and their Role in the Organization of Edge Activity

The capacity to break symmetry and organize activity to move directionally is a fundamental property of eukaryotic cells. To explain the organization of cell-edge activity, models commonly rely on front-to-back gradients of functional components or regulatory factors, but they do not explain how the front-back axis is defined in the first place. Recently, a novel and successful principle for self-organization of cell-edge activity was proposed, in which local cell-edge dynamics depends on the distance from the cell center, but not on the orientation with respect to the front-back axis. In this thesis, we test the hypothesis that edge motion is controlled by distance sensing via traction forces.\par We show that traction forces exerted on the substrate by polarizing cells are highly dynamical and follow motion of the cell-edge, that stress increases with the distance from the cell center and that maximal forces are located at a fixed distance from the edge near the sites of protrusion-retraction switches. We observe that traction forces correlate with edge extension in cell populations under different experimental conditions. We demonstrate with a fully mechanical model that distance dependence of the force is an emergent property of elastic fiber networks. We next show that dynamics of traction forces and cell-edge motion are correlated during protrusion-retraction cycles, indicating that traction forces trigger the switch from protrusion to retraction. Actin retrograde flow correlates with stress during retraction but not during protrusion suggesting that increase of stress during protrusion is independent of the motion of the actin network. Finally, incorporating a mechanism of cytoskeletal turnover in our model of fiber network we produce systems that display oscillatory fluctuations of their edge and other experimental behaviors.\par Our results provide strong evidence that traction forces play a major role in the organization of cell-edge activity and polarization.