Topological defects in epithelia govern cell death and extrusion

By T. B. Saw, A. Doostmohammadi, V. Nier, L. Kocgozlu, S. Thampi, Yusuke Toyama, P. Marcq, Chwee Teck Lim, Julia M. Yeomans, B. Ladoux. Nature, 2017

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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, oncogenic transformation and overcrowding of cells. Despite the important linkage of cell extrusion to developmental, homeostatic and pathological processes 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 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 activity, 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.

Subfields: Cell Biology, Condensed Matter Physics

View Paper: https://www.semanticscholar.org/paper/eae56dfdb045af6b409dc49cac8e00b0f3f2b70c

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Citations in the corpus

Symmetry, Thermodynamics, and Topology in Active Matter (2021, background): “Nematic order has now been reported in active systems on many scales, from subcellular structures, such as the mitotic spindle that controls cell division, to crawling bacteria [32– 34], epithelia [29, 35, 36], monolayers of vibrated granular rods [18] and even entire multicellular organisms [37].”
Topological active matter (2020, background): “Although defects in tissues have been noted as mechanically active centres of morphogenesis 71–73, 77 , current understanding of the interplay between active Active metamaterials and synthetic active matter also offer a platform for engineering topological states, with an eye to applications 8,135 .”