On the significance of membrane unfolding in mechanosensitive cell spreading: Its individual and synergistic effects

Mechanosensitivity of cell spread area to substrate stiffness has been established both through experiments and different types of mathematical models of varying complexity including both the mechanics and biochemical reactions in the cell. What has not been addressed in previous mathematical models is the role of cell membrane dynamics on cell spreading, and an investigation of this issue is the goal of this work. We start with a simple mechanical model of cell spreading on a deformable substrate and progressively layer mechanisms to account for the traction dependent growth of focal adhesions, focal adhesion induced actin polymerization, membrane unfolding/exocytosis and contractility. This layering approach is intended to progressively help in understanding the role each mechanism plays in reproducing experimentally observed cell spread areas. To model membrane unfolding we introduce a novel approach based on defining an active rate of membrane deformation that is dependent on membrane tension. Our modeling approach allows us to show that tension-dependent membrane unfolding plays a critical role in achieving the large cell spread areas experimentally observed on stiff substrates. We also demonstrate that coupling between membrane unfolding and focal adhesion induced polymerization works synergistically to further enhance cell spread area sensitivity to substrate stiffness. This enhancement has to do with the fact that the peripheral velocity of spreading cells is associated with contributions from the different mechanisms by either enhancing the polymerization velocity at the leading edge or slowing down of the retrograde flow of actin within the cell. The temporal evolution of this balance in the model corresponds to the three-phase behavior observed experimentally during spreading. In the initial phase membrane unfolding is found to be particularly important.