Multi-Cellular Modelling of Cellular Mechanisms Gives Insights on the Maintenance of Epidermal Tissue Structure

Abstract

The inter-follicular epidermis (IFE) forms the outer-most layer of the skin. Many individual components fundamental to healthy IFE structure are known: proliferation occurs only in a basal layer; above this layer cells differentiate into keratinocytes forming further distinct layers before they are shed from the surface. However, a definitive understanding of how the balance between proliferation, differentiation, and cell shedding is maintained in IFE tissue during homeostasis does not yet exist. We have developed an agent-based multi-cellular computational model to simulate tissue homeostasis in the skin. Epidermal cells are represented as overlapping spheres, and cell divisions are represented as stochastic time-driven events. Cell movement is determined by adhesive attractive forces and repulsive forces between other cells and the basal membrane. The magnitude of these forces depends upon the types of the interacting bodies, and can vary depending on factors such as cell age and location. Using this model we have analysed the impact of different cell mechanisms and behaviours on the tissue in order to investigate alternate hypotheses around maintenance of tissue structure. Mechanisms investigated include cell division, cell adhesion and stiffness, and cell death. Results of this study provide insights on important considerations in modelling this system. In particular, both choice of biological assumptions and the mathematical representation of cell division impact the spatial distribution of proliferative cell populations. We find that the cell mechanisms and behaviours critical to maintenance of the tissue width are proliferation rate, spatial adhesion variation, and cell loss.