Mechanical stress driven by rigidity sensing governs epithelial stability

Abstract

Epithelia act as a barrier against environmental stress and abrasion and in vivo they are continuously exposed to environments of various mechanical properties. The impact of this environment on epithelial integrity remains elusive. By culturing epithelial cells on 2D hydrogels, we observe a loss of epithelial monolayer integrity through spontaneous hole formation when grown on soft substrates. Substrate stiffness triggers an unanticipated mechanical switch of epithelial monolayers from tensile on soft to compressive on stiff substrates. Through active nematic modelling, we find that spontaneous half-integer defect formation underpinning large isotropic stress fluctuations initiate hole opening events. Our data show that monolayer rupture due to high tensile stress is promoted by the weakening of cell-cell junctions that could be induced by cell division events or local cellular stretching. Our results show that substrate stiffness provides feedback on monolayer mechanical state and that topological defects can trigger stochastic mechanical failure, with potential application towards a mechanistic understanding of compromised epithelial integrity during immune response and morphogenesis.

Structure and Rheology in Vertex Models under Cell-Shape-Dependent Active Stresses

“…3f) that is reminiscent of negative wake reported in driven yield-strain materials [49]. A similar negative wake flow pattern is visible in experiments on Madin-Darby Canine Kidney cell monolayers [33,50] (see SM [25], Sec. VIII).…”

“…There are different ways to translate the cellular bulk stresses σ (act) into the vertex forces F (act) i [33][34][35][36]. Here we use the approach proposed by Tlili et al [33,34,36], which relies on Cauchy's stress definition. For the cell shape anisotropy tensor Q J in Eq.…”

A morphogenic cascade emerges from the co-evolution of spheroid fluidization and fracturing of multicellular barriers

“…Besides the apical constriction mechanism, we use traction force microscopy (TFM) to analyze the contribution of in-plane traction-mediated migration of mesothelial cells during fracture 22,33 . First, we find that the spheroid's leader cell tends to contract the PDMS substrate in the absence of mesothelium (Fig.…”

Flow around topological defects in active nematic films

“…In addition to the characteristic flow fields, our closed form analytic descriptions provide an insight into the isotropic stress patterns, i.e., half of the trace of the stress tensor, around full-integer topological defects. Such isotropic stresses have been shown to be a determining factor for the biological functionality of nematic defects, where concentration of compressive stress around +1/2 defects was shown to lead to cell death and extrusion 27 , while the tensile stresses around −1/2 defects has been shown to lead to spontaneous gap opening in epithelial cell layers 49 . Similarly, we find distinct isotropic stress patterns around positive and negative full-integer defects: while around a negative (−1) defect alternating regions of tension and compression appear in a 4-fold symmetric pattern (Fig.…”