Agility in Mechanochemical Cellular Responses: Spatially-Localized Coupling of Cellular Control Modulates Traction Stresses and Retrograde Flow Within Cells

Abstract

While there have been numerous studies of cell spreading on substrates with different stiffnesses that have helped to elucidate the role of the actin cytoskeleton in cell protrusion and in focal adhesion (FA) evolution, there are still several questions that remain unanswered. Specifically, we focus on the effects of substrate stiffness on modulating the coupling between protrusive activity and actin retrograde flow and investigate how quantitative changes in this coupling modify actin dynamics, FA evolution, and cell spread areas. This will allow us to better understand effect of substrate stiffness on the biphasic relationship between retrograde flow and traction stresses observed by Gardel et al. (JCB, 2008). We present an axisymmetric model of a flat cell spreading on a two-dimensional substrate. The actin network is modeled as a viscous gel, and actin spreading and contraction dynamics are incorporated into the model as a local active rate of deformation. The model also incorporates stress-dependent FA dynamics, which in turn modulate a cell's protrusive activity and speed of actin retrograde flow, thereby controlling the spreading rate. Using this model, we are able to recapitulate the three phases of cell spreading dynamics described in Gianonne et al. (Cell, 2004), and we predict how the balance of protrusive activity, retrograde flow, FA strength, and local actomyosin contractions must change as the cell evolves through these three phases. We also show that increases in substrate stiffness lead to changes in retrograde flow rates and myosin concentrations, which can affect the localization of the biphasic relationship between retrograde flow rates and traction stresses as well as affecting the size and strength of FAs.