Computational modeling of actin-based fibroblast cell spreadin

This doctoral research is uses a computational approach to understand the mechanisms underlying the regulation of the isotropic spreading of a fibroblast cell by actin-based biochemical reactions in response to extracellular fibronectin molecules in a spatially dependent manner. The specific goals include: (1) development of a microscopic computational model that captures the inherent spatial and temporal stochasticity of actin-based cell motility machinery for the isotropic spreading of fibroblast cell; (2) studying the spatially and temporally dependent spreading velocity of fibroblast cell; (3) investigating how the concentrations of Arp2/3 and capping protein regulate the spreading velocity. To achieve these goals, I have (1) constructed an efficient stochastic model based on Gillespie's First Reaction Method to simulate the growth of actin cytoskeleton driven by filament polymerization, filament branching and filament capping reactions and the consequent protrusion of cell membrane generated by the growth of cytoskeletal network; (2) computed the spatial and temporal distribution of the spreading velocity of fibroblast cell and compared the simulation results with experimental measurements; (3) studied the dependency of cell spreading velocity on the molecular concentrations of Arp2/3 and capping protein and explained these dependencies at the level of the biochemical kinetics of filament reactions and the biophysical interactions between actin cytoskeleton and cell membrane. I find that: (1) the isotropic spreading of fibroblast cell shows large stochastic variations in both space and time under identical molecular conditions; (2) stochastic cell spreading is characterized by deterministic mean spreading velocity averaged in both space and time; (3) the spreading velocity of a fibroblast cell is regulated by the molecular concentrations of Arp2/3 and capping protein in a deterministic way. Overall this doctoral research provides insights into the molecular mechanisms and the biological functionalities of the actin-based motility machinery of the isotropic spreading of fibroblast cell, and how the spatial and temporal stochasticity can be converted into deterministic cell spreading behaviors.