Interplay between Cell Proliferation and Collective Behavior in Epithelia

Collections of epithelial cells form macroscopic materials which show collective behavior including 3D deformation, self-organization, and cell turnover. However, the complex cell-cell interactions in epithelia which drive collective behavior are not well understood. Therefore, we performed studies which aim to connect molecular pathways regulating the cytoskeleton and cell proliferation to cell-cell interactions and collective cell behavior. We quantitatively characterized tissue scale behaviors under different perturbations to cell signaling and used this data to develop new models of epithelia. Here we demonstrate that collective motion and self-organization in epithelia is driven in significant part by cell cycle dependent changes in cell-cell interactions. Conversely, we show that the cell cycle is regulated by collective behavior at the tissue scale through a process called contact inhibition of proliferation. We present a framework for explaining how cell proliferation is regulated by spatial constraints imposed by the epithelium which we then test experimentally. Together, these observations demonstrate that there is feedback between proliferative and collective cell behaviors in the epithelium that may play important roles in tissue morphogenesis and homeostasis. The data we present elucidate several general phenomena of epithelial tissues which may be observed across diverse tissue types and be relevant to understanding normal tissue function and disease states