Differential motility leads to intestinal organoid budding.

Intestinal organoids are complex three-dimensional formations that faithfully replicate the cellular composition and tissue arrangement characteristic of the digestive organ, the intestine. In vitro experiments have demonstrated that these organoids develop asymmetrical structures such as crypts and villi through self-organization and spherical symmetry breaking. In this study, we employ a minimal agent-based model to computationally investigate the dynamics of symmetry breaking within intestinal organoids, validating our findings against experimental observations. Our model conceptualizes the initial state of the organoid as a collection of proliferative, motile, soft-interacting particles configured in a spherical geometry, embedded within a viscoelastic extracellular matrix. We show that cell-to-cell variability of transiently activated YAP1 in a symmetrical sphere initiates DLL1 activation and first paneth cell formation that creates local inhomogeneity in the motility of the cells causing budding. To provide a theoretical understanding, we model the organoid as a continuous three-dimensional membrane characterized by membrane tension, bending stiffness, and tethering to the surrounding extracellular matrix. By defining the dynamics of membrane radial fluctuations and motile cell density fluctuations, linear stability analysis reveals that gradients in motility promote instability in lower modes supporting our computational and experimental results.