Physical aspects of epithelial cell-cell interactions: hidden system complexities

The maintenance of homeostasis and the retention of ordered epithelial cell self-organization are essential for morphogenesis, wound healing, and the spread of cancer across the epithelium. However, cell-cell interactions in an overcrowded environment introduce a diversity of complications. Such interactions arise from an interplay between the cell compressive and shear stress components that accompany increased cell packing density. They can lead to various kinds of cell rearrangement such as: the epithelial-to-mesenchymal cell state transition; live cell extrusion; and cell jamming. All of these scenarios of cell rearrangement under mechanical stress relate to changes in the strengths of the cell-cell and cell-matrix adhesion contacts. The objective of this review study is twofold: first, to provide a comprehensive summary of the biological and physical factors influencing the effects of cell mechanical stress on cell-cell interactions, and the consequences of these interactions for the status of cell-cell and cell-matrix adhesion contacts; and secondly, to offer a bio-physical/mathematical analysis of the aforementioned biological aspects. By presenting these two approaches in conjunction, we seek to highlight the intricate nature of biological systems, which manifests in the form of complex bio-physical/mathematical equations. Furthermore, the juxtaposition of these apparently disparate approaches underscores the importance of conducting experiments to determine the multitude of parameters that contribute to the development of these intricate bio-physical/mathematical models.