Lack of Neighbor Exchanges From Modulating Epithelial Cell Movement Through Division and Substrate Stiffness

Control over multicellular tissue has implications for morphogenesis, tissue repair, and disease progression. However, how the architecture and dynamics of multicellular tissue is controlled is largely unknown. Key to this control is cell-generated active stress which drives cell movement and shape change. Until recently, it was believed that the dominant stresses driving cell locomotion arise from substrate interactions involving focal-adhesion signaling with the extracellular matrix. However, recent work demonstrated that, under conditions with minimal focal-adhesion signaling, the cell cycle drives fluctuations at cell-cell interfaces. We explore the interplay between these two origins of active stress in epithelia by using cells whose cell cycle is stalled and by modifying the extracellular matrix to which the model tissue is attached. Intriguingly, we find that the cell cycle-dependent stresses generate large fluctuations of cell shape, but negligible cell-neighbor exchanges. Through varying culture conditions which modulate epithelial cell motility, we find little evidence of fluid-like states as suggested by the Vertex Model, a prevailing model for epithelial tissue dynamics. We explore instead other possible models to understand the full range of the experimental data.