(18b) A Computational Model Predicts the Three-Dimensional Homeostatic Structure and Dynamics of the Cellular Assembly in an Epithelial Organoid

The self-organization of cells into functional tissues is fundamental to development and wound-healing processes. In recent years, cultivation of organoids such as epithelial cysts in vitro has provided invaluable insights into collective cellular behavior and tissue dynamics. When epithelial cells are cultured within soft 3D extracellular matrices, they spontaneously grow and self-organize into a spherical monolayer of polarized cells encompassing a central fluid-filled lumen, providing a platform to study epithelial tissue in vitro. Here we describe a full three-dimensional computational finite element model of an epithelial cystic organoid that predicts the statics and dynamics of a cyst comprised of up to hundreds of individual cells, with each cell composed of five to seven quadratic wedge-shaped finite elements. Unlike previous vertex-based computational models of epithelial tissue, this finite element model is fully three-dimensional, accounting for the variable surface tensions and curvatures of the different cell faces, and the dynamic viscoelastic coupling between the motion of the various vertices and faces of the epithelial structure. The model predicts the three-dimensional homeostatic structure of the epithelial cyst, and dynamics of the structure when perturbed away from homeostasis. The model yields explanations for several puzzling experimental observations, such as: (1) why the curvature of lumen surfaces of cells in the monolayer is larger than that of the external surfaces; (2) how the cyst structure maintains mechanical equilibrium though tuning of the surface tension; (3) why the monolayer thickness is susceptible to oscillations; and (4) why increasing actomyosin contractility leads to collapse and eversion of the cyst structure, i.e. loss of lumen structure and movement of the lumen cell surfaces of the cells to the exterior of the cell cluster.