Integration of TGF-β- and EGFR-based signaling pathways using an agent-based model of epithelial restitution

Damage to an epithelial surface disrupts its mechanical and immunologic barrier function and exposes underlying tissues to a potentially hostile external environment. Epithelial restitution occurs quickly to reestablish the barrier and comprises a major part of the immediate host response to injured tissue. Pathways involving transforming growth factor beta and activation of epidermal growth factor receptor are both of critical importance, although cross-pathway interactions have been poorly characterized. Agent-based modeling has been showed to be useful in integrating disparate bodies of knowledge and showing the dynamic consequences of pathway structures and cellular population behavior and is used herein to create an in silico analog of an in vitro scratch assay. The In Vitro Scratch Agent-Based Model consists of agents representing individual epithelial cells in a simulated extracellular matrix. Agents sense signals from the damaged environment and produce effector molecules, leading to their healing behavior. The In Vitro Scratch Agent-Based Model qualitatively matched wound healing dynamics when compared against data from traditional experiments. Putative cross-talk mechanisms were then instantiated into the In Vitro Scratch Agent-Based Model and their relative plausibility examined, suggesting interaction at the receptor tyrosine kinase level. This highlights the utility of dynamic knowledge representation in the integration of pathways previously studied in separate contexts.