Agent-based computational modeling of wounded epithelial cell monolayers.

ABSTRACT

Computational modeling of biological systems, or in silico biology, is an emerging tool for understanding structure and order in biological tissues. Computational models of the behavior of epithelial cells in monolayer cell culture have been developed and used to predict the healing characteristics of scratch wounds made to urothelial cell cultures maintained in low- and physiological [Ca2+] environments. Both computational models and in vitro experiments demonstrated that in low exogenous [Ca2+], the closure of 500-microm scratch wounds was achieved primarily by cell migration into the denuded area. The wound healing rate in low (0.09 mM) [Ca2+] was approximately twice as rapid as in physiological (2 mM) [Ca2+]. Computational modeling predicted that in cell cultures that are actively proliferating, no increase in the fraction of cells in the S-phase would be expected, and this conclusion was supported experimentally in vitro by bromodeoxyuridine incorporation assay. We have demonstrated that a simple rule-based model of cell behavior, incorporating rules relating to contact inhibition of proliferation and migration, is sufficient to qualitatively predict the calcium-dependent pattern of wound closure observed in vitro. Differences between the in vitro and in silico models suggest a role for wound-induced signaling events in urothelial cell cultures.