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Multiscale regulation of epithelial tension

Final Report Summary - TENSIONCONTROL (Multiscale regulation of epithelial tension)

The main goal of TENSIONCONTROL was to study the mechanisms that control tension in epithelial tissues, the thin cell sheets that cover internal and external surfaces of our body. These sheets are two-dimensional active materials capable of performing a broad diversity of functions including morphogenesis, wound healing, tissue compartmentalization, and protection against environmental pathogens. Epithelial sheets carry out these functions in a dynamic mechanical environment characterized by elevated levels of cell and tissue tension. During epithelial morphogenesis, for example, cells experience several-fold changes in their surface area to enable the formation of complex three-dimensional shapes. During adult life, the epithelium of diverse organs functions routinely in the presence of significant levels of stretch such as those arising from breathing maneuvers, cardiac pulses, or peristaltic contractions. Under physiological conditions, stretch is a potent stimulus for growth, differentiation, secretion, remodeling, and gene expression. Failure to withstand stretch, however, causes epithelial fracture, which may lead to developmental defects and severe clinical conditions.

In TENSIONCONTROL we developed an integrated experimental setup to map and perturb tension within cell monolayers. We achieved this objective by combining experimental and computational methods. Specifically, we implemented new tools to synthesize soft hydrogels attached to stretchable silicon membranes, to micropattern cell monolayers on soft hydrogels, to map cell-substrate forces and cell-cell forces, and to apply subcellular perturbations in tension. With this technological suite we studied the mechanisms that regulate epithelia tension at different length scales. At the molecular scale we established how distinct proteins of the cell-cell adhesion complexes define cellular tension. At the cellular scale we showed that the mechanical properties of the actomyosin cortex are sufficient to explain the relationship between epithelial tension and deformation. This relationship displays super-elastic behavior, an unanticipated behavior in living systems. Finally, we showed that cell division and cell death both regulate epithelial tension, which is in turn predictive for the duration of the cell cycle. Together, our discoveries establish the importance of mechanical tension in regulating cellular function.