Topological defects in epithelia govern cell death and extrusion

By modelling epithelial cells as active nematic liquid crystals, stresses induced at the sites of topological defects are found to be the primary drivers of extrusion and cell death. A functional role for topological defects in epithelial monolayers Epithelial monolayers remove excess cells by extrusion. Benoit Ladoux and colleagues now report a purely mechanical route to cell extrusion at the site of topological defects within the cell monolayer. By modelling the epithelium as an active nematic liquid crystal, they show that cell extrusion is driven by stresses induced by distortions in cell orientation. Extrusion hotspots were controlled by geometrically inducing defects through microcontact printing of patterned monolayers. The authors also investigated the mechanotransductive effect of stress localization and found that signals related to cell death were induced at these sites of compressive stress. Additionally, tampering with the intercellular adhesion complexes led to a weakening of cell–cell interactions and resulted in an increased number of defects and extrusions. This finding is in line with nematic theory, which predicts that the number of topological defects is inversely related to the orientational elasticity. Epithelial tissues (epithelia) remove excess cells through extrusion, preventing the accumulation of unnecessary or pathological cells. The extrusion process can be triggered by apoptotic signalling 1 , oncogenic transformation 2 , 3 and overcrowding of cells 4 , 5 , 6 . Despite the important linkage of cell extrusion to developmental 7 , homeostatic 5 and pathological processes 2 , 8 such as cancer metastasis, its underlying mechanism and connections to the intrinsic mechanics of the epithelium are largely unexplored. We approach this problem by modelling the epithelium as an active nematic liquid crystal (that has a long range directional order), and comparing numerical simulations to strain rate and stress measurements within monolayers of MDCK (Madin Darby canine kidney) cells. Here we show that apoptotic cell extrusion is provoked by singularities in cell alignments 9 , 10 in the form of comet-shaped topological defects. We find a universal correlation between extrusion sites and positions of nematic defects in the cell orientation field in different epithelium types. The results confirm the active nematic nature of epithelia, and demonstrate that defect-induced isotropic stresses are the primary precursors of mechanotransductive r