Abstract
AbstractCell motility is important for many physiological processes and the underlyingbiochemical reactions motility have been well characterized. Mathematical models, usingthe biochemical reactions and focused on different types of spreading behavior have beenconstructed and analyzed. In this study, we build on these previous models to develop athree-dimensional stochastic model of isotropic spreading of mammalian fibroblasts. The model is composed of three actin remodeling reactions that occur stochastically in space and time and are regulated by membrane resistance forces. Numerical simulations indicate that the model qualitatively captures the experimentally observed isotropic cell spreading behavior. We analyzed the effects of varying branching reaction rates, membrane resistance forces and capping protein concentrations on the dynamics of isotropic spreading. The simulations allowed us to identify the range within which branching reaction rates and membrane force values cooperate to yield isotropic spreading behavior. The model predicts increasing capping protein concentration would lead to a linear decrease in average peripheral velocity. We tested this prediction experimentally using varying concentrations of a pharmacologic agent (Cytochalasin D) that caps growing actin filaments. We find that the experimental results agree with the numerical simulations. Thus, a spatio-temporally complex model made up of a simple set of stochastic reactions near the cell surface, when constrained by membrane forces, can yield deterministic behavior as characterized by isotropic cell spreading.
Highlights
Cell motility plays an important role in many physiological processes including responses to infection and wound healing
We have developed a three-dimensional stochastic model of actin polymerization, branching, and capping regulated by membrane resistance forces and conducted numerical simulations to generate spatial velocity distributions of the leading edge during cell spreading
When the membrane resistance force is maintained at 300 pN/μm2 (Figure 4A, Table 1) we begin to see spreading velocity distributions that are similar to isotropic cell spreading behavior as observed in experiments (Figure 2B)
Summary
Cell motility plays an important role in many physiological processes including responses to infection and wound healing. We hypothesized that the regulation of the actin filament remodeling reactions (polymerization, branching and capping) would be sufficient to generate dynamics similar to the experimentally observed behavior of fibroblasts spreading on fibronectin coated glass surfaces.
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