title: Topological defects in epithelia govern cell death and extrusion.
abstract: 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.
authors.affiliation: Mechanobiology Institute, National University of Singapore, Singapore.|National University of Singapore Graduate School of Integrative Sciences and Engineering (NGS), National University of Singapore, Singapore.
authors.forename: Thuan Beng
authors.initials: TB
authors.lastname: Saw
authors.affiliation: The Rudolf Peierls Centre for Theoretical Physics, Oxford University, UK.
authors.forename: Amin
authors.initials: A
authors.lastname: Doostmohammadi
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6, Institut Curie, CNRS, UMR 168, Laboratoire Physico-Chimie Curie, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Nier
authors.affiliation: Mechanobiology Institute, National University of Singapore, Singapore.
authors.forename: Leyla
authors.initials: L
authors.lastname: Kocgozlu
authors.affiliation: The Rudolf Peierls Centre for Theoretical Physics, Oxford University, UK.|Department of Chemical Engineering, Indian Institute of Technology Madras, Chennai, India.
authors.forename: Sumesh
authors.initials: S
authors.lastname: Thampi
authors.affiliation: Mechanobiology Institute, National University of Singapore, Singapore.|Department of Biological Sciences, National University of Singapore, and Temasek Life Sciences Laboratory, Singapore.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6, Institut Curie, CNRS, UMR 168, Laboratoire Physico-Chimie Curie, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marcq
authors.affiliation: Mechanobiology Institute, National University of Singapore, Singapore.|National University of Singapore Graduate School of Integrative Sciences and Engineering (NGS), National University of Singapore, Singapore.
authors.forename: Chwee Teck
authors.initials: CT
authors.lastname: Lim
authors.affiliation: The Rudolf Peierls Centre for Theoretical Physics, Oxford University, UK.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Yeomans
authors.affiliation: Mechanobiology Institute, National University of Singapore, Singapore.|Institut Jacques Monod (IJM), CNRS UMR 7592 & Université Paris Diderot, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Ladoux
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002450:Cell Communication; D016923:Cell Death; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D007365:Intercellular Junctions / Q000378:metabolism; D050866:Liquid Crystals; D061985:Madin Darby Canine Kidney Cells; D040542:Mechanotransduction, Cellular; D008954:Models, Biological; D014157:Transcription Factors / Q000378:metabolism; D051178:alpha Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014157:Transcription Factors; D051178:alpha Catenin; D053148:Caspase 3