Mechanical stress driven by rigidity sensing governs epithelial stability

Epithelia act as barriers against environmental stresses. They are continuously exposed to various mechanical stress and abrasion, which impact epithelial integrity. The impact of the environment on epithelial integrity remains elusive. By culturing epithelial cells on two-dimensional hydrogels, we observe a loss of epithelial monolayer integrity on soft substrates through spontaneous hole formation. These monolayer ruptures are associated with local cellular stretching and cell-division events. Substrate stiffness triggers an unanticipated mechanical switch of epithelial monolayers from compressive stress on stiff substrates to highly tensile on soft, favouring hole formation. In agreement with an active nematic model, hole-opening events occur preferentially near spontaneous half-integer topological defects, which underpin large isotropic stress fluctuations triggering stochastic mechanical failure. Our results thus show that substrate stiffness provides feedback on the mechanical state of epithelial monolayers with potential application towards a mechanistic understanding of compromised epithelial integrity during normal and pathological human ontogenesis.