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. 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 signalling1, oncogenic transformation2,3 and overcrowding of cells4,5,6. Despite the important linkage of cell extrusion to developmental7, homeostatic5 and pathological processes2,8 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 alignments9,10 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 responses in cells, including YAP (Yes-associated protein) transcription factor activity11, caspase-3-mediated cell death, and extrusions. Importantly, the defect-driven extrusion mechanism depends on intercellular junctions, because the weakening of cell–cell interactions in an α-catenin knockdown monolayer reduces the defect size and increases both the number of defects and extrusion rates, as is also predicted by our model. We further demonstrate the ability to control extrusion hotspots by geometrically inducing defects through microcontact printing of patterned monolayers. On the basis of these results, we propose a mechanism for apoptotic cell extrusion: spontaneously formed topological defects in epithelia govern cell fate. This will be important in predicting extrusion hotspots and dynamics in vivo, with potential applications to tissue regeneration and the suppression of metastasis. Moreover, we anticipate that the analogy between the epithelium and active nematic liquid crystals will trigger further investigations of the link between cellular processes and the material properties of epithelia.

In this article, ultrafine gelatin (Gt) fibers were successfully produced with the use of the electrical spinning or electrospinning technique. A fluorinated alcohol of 2,2,2‐trifluoroethanol (TFE) was used as the dissolving solvent. The morphology of the electrospun gelatin fibers was found to be dependent on the alteration of gelatin concentration ranging from 2.5% w/v to 12.5% w/v at 2.5% increment intervals. Based on the electrospun gelatin fibers obtained, 10% w/v gelatin/TFE solution was selected and mixed with 10% w/v poly(ϵ‐caprolactone) (PCL) in TFE at a ratio of 50:50 and co‐electrospun to produce gelatin/PCL composite membranes. Contact‐angle measurement and tensile tests indicated that the gelatin/PCL complex fibrous membrane exhibited improved mechanical properties as well as more favorable wettability than that obtained from either gelatin or PCL alone. The gelatin/PCL fibrous membranes were further investigated as a promising scaffold for bone‐marrow stromal cell (BMSC) culture. Scanning electron microscopy (SEM) and laser confocal microscopy observations showed that the cells could not only favorably attach and grow well on the surface of these scaffolds, but were also able to migrate inside the scaffold up to 114 μm within 1 week of culture. These results suggest the potential of using composite gelatin/PCL fibrous scaffolds for engineering three‐dimensional tissues. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 72B: 156–165, 2005