Raphael Marcelpoil

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.

Cellular Sociology: Parametrization of Spatial Relationships Based on Voronoi Diagram and Ulam Trees

At all levels (molecules, cells, organisms, ...), biological systems are made of structural and functional units. Those units are interacting with each other and, tend to use space in an optimal way with respect to their specific function and environmental constraints. Hence, cells can be defined as being the smallest structural and functional units capable of auto-reproduction. The rapid technological advances during the 20th century have made possible to describe the inner architecture of cells at different levels of organization. Our approach is an attempt to study cellular populations at the “sociological” level, i.e. at the level of their spatial organization and interrelationship in a given tissue. The topographies of cellular population have to be considered linked to morphogenesis, structural stabilities and functional state of a given tissue. This approach makes use of the relations that links form to disorder and is based on space partition constructed from a set of points defining the position of cells. This spatial partition consisting of a set of individual forms (Voronoi paving) associated to its dual (Delaunay triangulation) permits the calculation of Ulam trees which are descriptors of the local surrounding of a given cell and the search for characteristic features of the normal and pathological state.