Cell cycle dependent mechanics drive epithelial stratification

Epithelia have multiple spatial domains which perform specific tasks, e.g. crypts and villi in the intestine. This spatial organization can be disrupted in disease and is often associated with loss of tissue function. One of the key differences between these compartments is that some are highly proliferative, while others contain mainly non-proliferative cells. Cells drastically change their proliferation rates when they differentiate and move between these compartments, however, it remains unclear how these differences in proliferation affect epithelial organization. Here we focus on skin as a model system which can build these compartments starting from a single layer of stem cells. We heterogeneously express cell cycle inhibitors during the formation of skin organoids to measure how perturbing proliferation can change the organization of cells in the skin. We show that cells which become arrested in the cell cycle are more likely to exit the stem cell layer. By measuring contacts between cell-cell and cell-substrate interfaces we show that cell mechanics and adhesion are altered during the cell cycle. Together with theoretical modeling we show that these cell cycle dependent changes in cortical mechanics are an important driver of cell organization in the skin.