Epithelial cells form continuous sheets of cells that exist in tensional homeostasis. Homeostasis is maintained through cell-to-cell adhesions that distribute tension and balance forces between cells and their underlying matrix. Disruption of tensional homeostasis can lead to Epithelial-Mesenchymal Transition (EMT), which is a transdifferentiation process in which epithelial cells adopt a mesenchymal phenotype, where cell-cell adhesion is lost and individual cell migration is acquired. This process is critical during embryogenesis and wound healing, but is also dysregulated in many disease states. To further understand the role of intercellular tension in spatial patterning of epithelial cell monolayers, we developed a multicellular computational model of cell-cell and cell-substrate forces. This work builds on a hybrid Cellular Potts-finite element model to evaluate cell-matrix mechanical feedback of an adherent multicellular cluster. Thermodynamically-constrained cells migrate by generating traction forces on a finite element substrate to minimize the total energy of the system. Junctional forces at cell-cell contacts balance these traction forces, thereby producing a mechanically stable epithelial monolayer. Simulations were compared to in vitro experiments using fluorescence-based junction force sensors in clusters of cells undergoing EMT. Results indicate that the multicellular CPM model can reproduce many aspects of EMT, including epithelial monolayer formation dynamics, changes in cell geometry, and spatial patterning of cell geometry and cell-cell forces in an epithelial colony.

A Predictive Model of Intercellular Tension and Cell-Matrix Mechanical Interactions in a Multicellular Geometry