Tissue geometry encodes a surface tension gradient that drives epithelial renewal

Abstract

The mammalian intestinal epithelium renews itself every few days through coordinated cell movement and extrusion along the crypt-villus axis, yet how these processes are physically organized across intact tissue remains unknown. Using long-term live imaging of intact intestinal tissue, nuclear strain mapping, and targeted perturbations of cell-cell adhesion, actomyosin contractility, and extracellular matrix adhesion, we find that epithelial cells experience a graded mechanical landscape encoded by villus geometry; tension is highest at the villus tip and decays toward the base. This tissue-scale tension gradient, generated by E-cadherin-mediated adhesion and actomyosin contractility, is the dominant predictor of collective cell velocity, outperforming force magnitude and cell density. Artificial re-establishment of a tension gradient is sufficient to reorient epithelial migration, whereas disruption of the gradient arrests both cell movement and extrusion. Epithelial renewal further requires a precise balance between this tension gradient and extracellular matrix-derived friction; excessive friction uncouples migration from extrusion, leading to pathological cell accumulation. Together, these findings reveal that intestinal epithelial homeostasis is organized by a geometry-encoded mechanical gradient that coordinates collective cell motion, extrusion, and tissue repair through a single tissue-scale framework.