Emergent intercellular junction stability during cyclic tissue loading.

Abstract

Epithelial tissues are often exposed to cyclic deformations in their physiological environment. Maintenance of mechanical integrity relies on intercellular adhesion proteins that link neighboring cells and transmit forces across the cellular network. The stability of these intercellular adhesion complexes is therefore critical for tissue strength. Under sustained stress, failure of intercellular adhesion complexes leads to damage accumulation that progressively weakens the material and ultimately causes failure at the tissue scale. Although the collective behavior of adhesion complexes under static loading has been characterized to some extent, their response to dynamic loading remains largely unknown, despite its physiological importance. Here, we combine quantitative experiments on Madin-Darby Canine Kidney monolayers with modeling of intercellular adhesion complexes with force-dependent detachment rates to investigate tissue resilience under cyclic loading. We find that cyclic loading significantly prolongs tissue lifetime and increases the maximum deformation the tissue can withstand before failure compared with constant tension, thanks to repair occurring during low-tension phases. Our model identifies intrinsic rupture and repair timescales governing adhesion stability, revealing three regimes of tissue behavior: rupture, slow damage accumulation, and stable equilibrium. Normalizing loading parameters by the intrinsic material timescales collapse experimental and simulated data into universal stability maps. These findings demonstrate that epithelial resilience emerges from stochastic adhesion bond dynamics, providing a predictive framework linking adhesion complex turnover to macroscopic tissue mechanics under physiological cyclic forces.