A proliferation control network model: the simulation of two-dimensional epithelial homeostasis.

Despite the recent progress in the description of the molecular mechanisms of proliferation and differentiation controls in vitro, the regulation of the homeostasis of normal stratified epithelia remains unclear in vivo. Computer simulation represents a powerful tool to investigate the complex field of cell proliferation regulation networks. It provides huge computation capabilities to test, in a dynamic in silico context, hypotheses about the many pathways and feedback loops involved in cell growth and proliferation controls. Our approach combines a model of cell proliferation and a spatial representation of cells in 2D using the Voronoi graph. The cell proliferation model includes intracellular (cyclins, Cyclin Dependent Kinases - CDKs. Retinoblastoma protein - Rb, CDK inhibitors) and extracellular controls (growth and differentiation factors, integrins). The Voronoi graph associates a polygon with every cell and the set of these polygons defines the tissue architecture. Thus, the model provides a quantitative model of extracellular signals and cell motility as a function of the neighborhood during time dependent simulations. The 2D simulations illustrate the influence of the microenvironment on cell proliferation in basal layers of stratified epithelia and of differential adherence in keratinocytes differentiation and related upward migration. Our results particularly show the role of CDK inhibitors (mainly the protein p27) in the Rb dependent control pathway of the transition from the G1 to S phase of the cell cycle.