Cell cycle-dependent active stress drives epithelia remodeling

Abstract

Epithelia have distinct cellular architectures, which are established in development, re-established after wounding, and maintained during tissue homeostasis despite cell turnover and mechanical perturbations. In turn, cell shape also controls tissue function as a regulator of cell differentiation, proliferation, and motility. Here we investigate cell shape changes in a model epithelial monolayer. After the onset of confluence, cells continue to proliferate and change shape over time, eventually leading to a final architecture characterized by arrested motion and more regular cell shapes. Such monolayer remodeling is robust, with qualitatively similar evolution in cell shape and dynamics observed across disparate perturbations. Here we quantify differences in monolayer remodeling guided by the active vertex model to identify underlying order parameters controlling epithelial architecture. When monolayers are formed atop extracellular matrix with varied stiffness, we find the cell density at which motion arrests varies significantly but the cell shape remains constant, consistent with the onset of tissue rigidity. In contrast, pharmacological perturbations can significantly alter the cell shape at which tissue dynamics is arrested, consistent with varied amounts of active stress within the tissue. Across all experimental conditions the final cell shape is well correlated to the cell proliferation rate, and cell cycle inhibition immediately arrests cell motility. Finally, we demonstrate cell-cycle variation in junctional tension as a source of active stress within the monolayer. Thus, the architecture and mechanics of epithelial tissue can arise from an interplay between cell mechanics and stresses arising from cell cycle dynamics. SIGNIFICANCE STATEMENTThe morphology of biological tissue is determined by the shape and density of constituent cells. Here we measure the dynamics of cells in model epithelial tissues to study the evolution of their shape and density over time. Guided by a mathematical model, we find that cell shape is controlled by rigidity and active stresses within the tissue. We then show that cell cycle dynamics are the source of active stress that drives epithelial remodeling.