The mechanical influence of densification on epithelial architecture

Epithelial tissues are the most abundant tissue type in animals, lining body cavities and generating compartment barriers. The function of a monolayered epithelial tissue-whether protective, secretory, absorptive, or filtrative-relies on the side-by-side arrangement of its component cells. The mechanical parameters that determine the shape of epithelial cells in the apical-basal plane are not well-understood. Epithelial tissue architecture in culture is intimately connected to cell density, and cultured layers transition between architectures as they proliferate. This prompted us to ask to what extent epithelial architecture emerges from two mechanical considerations: A) the constraints of densification and B) cell-cell adhesion, a hallmark feature of epithelial cells. To address these questions, we developed a novel polyline cell-based computational model and used it to make theoretical predictions about epithelial architecture upon changes to density and cell-cell adhesion. We tested these predictions using cultured cell experiments. Our results show that the appearance of extended lateral cell-cell borders in culture arises as a consequence of crowding-independent of cell-cell adhesion. However, cadherin-mediated cell-cell adhesion is associated with a novel architectural transition. Our results suggest that this transition represents the initial appearance of a distinctive epithelial architecture. Together our work reveals the distinct mechanical roles of densification and adhesion to epithelial layer formation and provides a novel theoretical framework to understand the less well-studied apical-basal plane of epithelial tissues. Epithelial tissues have critical functions in animal bodies-including protection, secretion, absorption, and filtration. To perform these functions, the component cells that make up the tissue must maintain their shape and organization. Loss of epithelial tissue organization leads to disease such as cancerous carcinoma. In this study, we explored the biophysical factors that drive epithelial shape using a combination of computational modelling and experimental studies. As cultured cells proliferate and consequently densify, they undergo a series of developmental transitions before achieving a mature architecture. Given the relationship between architecture and cell density, we asked to what extent cell crowding alone can explain the developmental transitions observed. We find that while crowding is sufficient to explain the initial feature of architecture development, namely the appearance of cell height, subsequent transitions also rely on cell-cell adhesion, a hallmark feature of epithelia.