Topological defects in epithelia govern cell death and extrusion
Open accessAbstract
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.
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The engineer's approach is to pursue simpler reductionist models defined by minimal functional modules (MFMs) that drive a complex cellular or tissue FOI, to study mechanobiological causation or develop robust systems for high throughput screening.
“On the other hand, the engineer’s (cell as a machine) approach28,247 is to pursue simpler reductionist models defined by the minimal functional modules (MFMs) that drive a complex cellular or tissue FOI, to study the mechanobiological causation in development or repair, or to develop a robust system for high throughput screening.”
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Cites
The Physics of Liquid Crystals
de Gennes, P. G., Prost, J., & Pelcovits, R. A. (1995) · Physics Today · doi:10.1063/1.2808028 · Cited by 9,810 · see citing works
Role of YAP/TAZ in mechanotransduction
Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Le Digabel, J., Forcato, M., Bicciato, S., et al. (2011) · Nature · doi:10.1038/nature10137 · Cited by 5,979 · see citing works
Analysis of Discrete Ill-Posed Problems by Means of the L-Curve
Hansen, P. C. (1992) · SIAM Review · doi:10.1137/1034115 · Cited by 3,903 · see citing works
Hecht, F. (2012) · Journal of Numerical Mathematics · doi:10.1515/jnum-2012-0013 · Cited by 3,500 · see citing works
PIVlab – Towards User-friendly, Affordable and Accurate Digital Particle Image Velocimetry in MATLAB
Thielicke, W., & Stamhuis, E. J. (2014) · Journal of Open Research Software · doi:10.5334/jors.bl · Cited by 2,408 · see citing works
Statistical and Computational Inverse Problems
Kaipio, J. P., & Somersalo, E. (2005) · Applied mathematical sciences · doi:10.1007/b138659 · Cited by 2,404 · see citing works
Elucidation of a universal size-control mechanism in Drosophila and mammals
Dong, J., Feldmann, G., Huang, J., Wu, S., Zhang, N., Comerford, S. A., Gayyed, M. F., Anders, R. A., Maitra, A., & Pan, D. (2007) · Cell · doi:10.1016/j.cell.2007.07.019 · Cited by 2,370 · see citing works
Aragona, M., Panciera, T., Manfrin, A., Giulitti, S., Michielin, F., Elvassore, N., Dupont, S., & Piccolo, S. (2013) · Cell · doi:10.1016/j.cell.2013.07.042 · Cited by 1,651 · see citing works
Spontaneous motion in hierarchically assembled active matter
Sanchez, T. H., Chen, D. T. N., DeCamp, S. J., Heymann, M., & Dogic, Z. (2012) · Nature · doi:10.1038/nature11591 · Cited by 1,419 · see citing works
Rezakhaniha, R., Agianniotis, A., Schrauwen, J. T. C., Griffa, A., Sage, D., Bouten, C. V. C., van de Vosse, F. N., Unser, M. A., & Stergiopulos, N. (2011) · Biomechanics and Modeling in Mechanobiology · doi:10.1007/s10237-011-0325-z · Cited by 1,104 · see citing works
α-Catenin as a tension transducer that induces adherens junction development
Yonemura, S., Wada, Y., Watanabe, T., Nagafuchi, A., & Shibata, M. (2010) · Nature Cell Biology · doi:10.1038/ncb2055 · Cited by 972 · see citing works
Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia
Eisenhoffer, G. T., Loftus, P. D., Yoshigi, M., Otsuna, H., Chien, C.-B., Morcos, P. A., & Rosenblatt, J. (2012) · Nature · doi:10.1038/nature10999 · Cited by 876 · see citing works
Fluid dynamics and noise in bacterial cell–cell and cell–surface scattering
Drescher, K., Dunkel, J., Cisneros, L. H., Ganguly, S., & Goldstein, R. E. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019079108 · Cited by 789 · see citing works
Force mapping in epithelial cell migration
du Roure, O., Saez, A., Buguin, A., Austin, R. H., Chavrier, P., Silberzan, P., & Ladoux, B. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408482102 · Cited by 780 · see citing works
Self-citationProst, J., Jülicher, F., & Joanny, J. (2015) · Nature Physics · doi:10.1038/nphys3224 · Cited by 744 · see citing works
Rosenblatt, J., RAFF, M. C., & Cramer, L. P. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00587-5 · Cited by 602 · see citing works
Fluid Mechanics of Planktonic Microorganisms
Guasto, J., Rusconi, R., & Stocker, R. (2011) · Annual Review of Fluid Mechanics · doi:10.1146/annurev-fluid-120710-101156 · Cited by 517 · see citing works
Quantifying cell-generated mechanical forces within living embryonic tissues
Campàs, O., Mammoto, T., Hasso, S. M., Sperling, R. A., O'Connell, D., Bischof, A. G., Maas, R. L., Weitz, D. A., Mahadevan, L., & Ingber, D. E. (2013) · Nature Methods · doi:10.1038/nmeth.2761 · Cited by 479 · see citing works
Emerging modes of collective cell migration induced by geometrical constraints
Vedula, S. R. K., Leong, M. C., Lai, T. L., Hersen, P., Kabla, A., Lim, C. T., & Ladoux, B. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1119313109 · Cited by 459 · see citing works
Self-citationForces driving epithelial wound healing
Brugués, A., Anon, E., Conte, V., Veldhuis, J. H., Gupta, M., Colombelli, J., Muñoz, J. J., Brodland, G. W., Ladoux, B., & Trepat, X. (2014) · Nature Physics · doi:10.1038/nphys3040 · Cited by 449 · see citing works
Self-citationLive-cell delamination counterbalances epithelial growth to limit tissue overcrowding
Marinari, E., Mehonic, A., Curran, S., Gale, J. E., Duke, T. A. J., & Baum, B. (2012) · Nature · doi:10.1038/nature10984 · Cited by 426 · see citing works
von Toussaint, U. (2011) · Reviews of Modern Physics · doi:10.1103/revmodphys.83.943 · Cited by 422 · see citing works
Characterizing the mechanics of cultured cell monolayers
Harris, A. R., Peter, L., Bellis, J., Baum, B., Kabla, A., & Charras, G. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1213301109 · Cited by 387 · see citing works
Characterization of the interface between normal and transformed epithelial cells
Hogan, C., Dupré‐Crochet, S., Norman, M., Kajita, M., Zimmermann, C., Pelling, A. E., Piddini, E., Baena-López, L. A., Vincent, J., Itoh, Y., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1853 · Cited by 362 · see citing works
Biomechanical ordering of dense cell populations
Volfson, D., Cookson, S., Hasty, J., & Tsimring, L. S. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706805105 · Cited by 311 · see citing works
Apoptotic Force and Tissue Dynamics During Drosophila Embryogenesis
Toyama, Y., Peralta, X. G., Wells, A. R., et al. (2008) · Science · doi:10.1126/science.1157052 · Cited by 309 · see citing works
Self-citationTopological defects in confined populations of spindle-shaped cells
Duclos, G., Erlenkämper, C., Joanny, J., et al. (2016) · Nature Physics · doi:10.1038/nphys3876 · Cited by 304 · see citing works
Marenduzzo, D., Orlandini, E., Cates, M. E., et al. (2007) · Physical Review E · doi:10.1103/physreve.76.031921 · Cited by 303 · see citing works
Tissue Crowding Induces Caspase-Dependent Competition for Space
Levayer, R., Dupont, C., & Moreno, E. (2016) · Current Biology · doi:10.1016/j.cub.2015.12.072 · Cited by 244 · see citing works
Tambe, D. T., Croutelle, U., Trepat, X., Park, C. Y., Kim, J. H., Millet, E. J., Butler, J. P., & Fredberg, J. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055172 · Cited by 226 · see citing works
Mechanical cell competition kills cells via induction of lethal p53 levels
Wagstaff, L., Goschorska, M., Kozyrska, K., Duclos, G., Kuciński, I., Chessel, A., Hampton-O’Neil, L. A., Bradshaw, C. R., Allen, G. E., Rawlins, E. L., et al. (2016) · Nature Communications · doi:10.1038/ncomms11373 · Cited by 216 · see citing works
Epithelial bridges maintain tissue integrity during collective cell migration
Vedula, S. R. K., Hirata, H., Nai, M. H., Brugués, A., Toyama, Y., Trepat, X., Lim, C. T., & Ladoux, B. (2013) · Nature Materials · doi:10.1038/nmat3814 · Cited by 196 · see citing works
Self-citationStabilization of active matter by flow-vortex lattices and defect ordering
Doostmohammadi, A., Adamer, M. F., Thampi, S. P., et al. (2016) · Nature Communications · doi:10.1038/ncomms10557 · Cited by 179 · see citing works
Self-citationDefect-Mediated Morphologies in Growing Cell Colonies
Doostmohammadi, A., Thampi, S. P., & Yeomans, J. M. (2016) · Physical Review Letters · doi:10.1103/physrevlett.117.048102 · Cited by 178 · see citing works
Self-citationInstabilities and topological defects in active nematics
Thampi, S. P., Golestanian, R., & Yeomans, J. M. (2014) · Europhysics Letters (EPL) · doi:10.1209/0295-5075/105/18001 · Cited by 156 · see citing works
Self-citationMeasurement of cell traction forces with ImageJ
Martiel, J., Leal‐Egaña, A., Kurzawa, L., Balland, M., Wang, I., Vignaud, T., Tseng, Q., & Théry, M. (2015) · Methods in cell biology · doi:10.1016/bs.mcb.2014.10.008 · Cited by 142 · see citing works
Epithelial repair is a two-stage process driven first by dying cells and then by their neighbours
Kuipers, D., Mehonic, A., Kajita, M., et al. (2014) · Journal of Cell Science · doi:10.1242/jcs.138289 · Cited by 139 · see citing works
Vorticity, defects and correlations in active turbulence
Thampi, S. P., Golestanian, R., & Yeomans, J. M. (2014) · Philosophical Transactions of the Royal Society A Mathematical Physical and Engineering Sciences · doi:10.1098/rsta.2013.0366 · Cited by 135 · see citing works
Self-citationTumour cell invasion: an emerging role for basal epithelial cell extrusion
Slattum, G. M., & Rosenblatt, J. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3767 · Cited by 134 · see citing works
Spontaneous flow states in active nematics: A unified picture
Edwards, S., & Yeomans, J. M. (2009) · Europhysics Letters (EPL) · doi:10.1209/0295-5075/85/18008 · Cited by 133 · see citing works
Self-citationBiphasic, Lyotropic, Active Nematics
Blow, M. L., Thampi, S. P., & Yeomans, J. M. (2014) · Physical Review Letters · doi:10.1103/physrevlett.113.248303 · Cited by 132 · see citing works
Self-citationExcitable Patterns in Active Nematics
Giomi, L., Mahadevan, L., Chakraborty, B., et al. (2011) · Physical Review Letters · doi:10.1103/physrevlett.106.218101 · Cited by 123 · see citing works
Border Forces and Friction Control Epithelial Closure Dynamics
Cochet‐Escartin, O., Ranft, J., Silberzan, P., & Marcq, P. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2013.11.015 · Cited by 119 · see citing works
Self-citationLattice Boltzmann algorithm for three–dimensional liquid–crystal hydrodynamics
Denniston, C., Marenduzzo, D., Orlandini, E., et al. (2004) · Philosophical Transactions of the Royal Society A Mathematical Physical and Engineering Sciences · doi:10.1098/rsta.2004.1416 · Cited by 116 · see citing works
Epithelial Cell Packing Induces Distinct Modes of Cell Extrusions
Kocgozlu, L., Saw, T. B., Le, A. P., Yow, I., Shagirov, M., Wong, E., Mège, R., Lim, C. T., Toyama, Y., & Ladoux, B. (2016) · Current Biology · doi:10.1016/j.cub.2016.08.057 · Cited by 113 · see citing works
Self-citationDoostmohammadi, A., Thampi, S. P., Saw, T. B., et al. (2015) · Soft Matter · doi:10.1039/c5sm01382h · Cited by 110 · see citing works
Self-citationNonlinear dynamics and rheology of active fluids: Simulations in two dimensions
Fielding, S. M., Marenduzzo, D., & Cates, M. E. (2011) · Physical Review E · doi:10.1103/physreve.83.041910 · Cited by 98 · see citing works
Topological defects and density fluctuations in collectively moving systems
Schaller, V., & Bausch, A. R. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1215368110 · Cited by 97 · see citing works
Inference of Internal Stress in a Cell Monolayer
Nier, V., Jain, S., Lim, C. T., Ishihara, S., Ladoux, B., & Marcq, P. (2016) · Biophysical Journal · doi:10.1016/j.bpj.2016.03.002 · Cited by 93 · see citing works
Self-citationDynamics of anisotropic tissue growth
Bittig, T., Wartlick, O., Kicheva, A., et al. (2008) · New Journal of Physics · doi:10.1088/1367-2630/10/6/063001 · Cited by 81 · see citing works
Chiba, T., Ishihara, E., Miyamura, N., et al. (2016) · Scientific Reports · doi:10.1038/srep28383 · Cited by 71 · see citing works
Mechanical Control of Cell flow in Multicellular Spheroids
Delarue, M., Montel, F., Caën, O., Elgeti, J., Siaugue, J., Vignjevic, D. M., Prost, J., Joanny, J., & Cappello, G. (2013) · Physical Review Letters · doi:10.1103/physrevlett.110.138103 · Cited by 70 · see citing works
FogBank: a single cell segmentation across multiple cell lines and image modalities
Chalfoun, J., Majurski, M. P., Dima, A. A., Stuelten, C. H., Peskin, A. P., & Brady, M. (2014) · BMC Bioinformatics · doi:10.1186/s12859-014-0431-x · Cited by 67 · see citing works
Long-range ordered vorticity patterns in living tissue induced by cell division
Rossen, N. S., Tarp, J. M., Mathiesen, J., et al. (2014) · Nature Communications · doi:10.1038/ncomms6720 · Cited by 64 · see citing works
Morphology transition in lipid vesicles due to in-plane order and topological defects
Hirst, L. S., Ossowski, A., Fraser, M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1213994110 · Cited by 63 · see citing works
Undulation Instability of Epithelial Tissues
Basan, M., Joanny, J., Prost, J., et al. (2011) · Physical Review Letters · doi:10.1103/physrevlett.106.158101 · Cited by 62 · see citing works
Kemkemer, R., Teichgräber, V., Schrank-Kaufmann, S., et al. (2000) · The European Physical Journal E · doi:10.1007/s101890070023 · Cited by 47 · see citing works
Quantification of growth asymmetries in developing epithelia
Bittig, T., Wartlick, O., González‐Gaitán, M., et al. (2009) · The European Physical Journal E · doi:10.1140/epje/i2009-10507-6 · Cited by 41 · see citing works
Distribution of singularities in the cosmic microwave background polarization
Huterer, D., & Vachaspati, T. (2005) · Physical review. D. Particles, fields, gravitation, and cosmology/Physical review. D. Particles and fields · doi:10.1103/physrevd.72.043004 · Cited by 34 · see citing works
Microfabricated Environments to Study Collective Cell Behaviors
Vedula, S. R. K., Ravasio, A., Anon, E., Chen, T., Peyret, G., Ashraf, M., & Ladoux, B. (2014) · Methods in cell biology · doi:10.1016/b978-0-12-417136-7.00016-1 · Cited by 33 · see citing works
Self-citationIntracellular stresses in patterned cell assemblies
Moussus, M., Loughian, C. D., Fuard, D., Courçon, M., Gulino-Debrac, D., Delanoë‐Ayari, H., & Nicolas, A. (2013) · Soft Matter · doi:10.1039/c3sm52318g · Cited by 26 · see citing works
The effective film viscosity coefficients of a thin floating fluid layer
Jenkins, A. D., & Dysthe, K. B. (1997) · Journal of Fluid Mechanics · doi:10.1017/s0022112097006125 · Cited by 20 · see citing works
Tambe, D. T., Croutelle, U., Trepat, X., et al. (2014) · PLoS ONE · doi:10.1371/annotation/d29aed40-7667-4901-8008-ef473c363216 · Cited by 2 · see citing works
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Research works printed but not linked: 2
- [48]Prost J The physics of liquid crystals Oxford University Press 1995
- [49]Larson RG The structure and rheology of complex fluids Oxford University Press New York 1999 33
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Zhao, Z., Chen, X., Dowbaj, A. M., Sljukic, A., Bratlie, K., Lin, L., Fong, E. L. S., Balachander, G. M., Chen, Z., Soragni, A., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-022-00174-y · Cited by 1,001 · see citing works
Mechanobiology of collective cell behaviours
Ladoux, B., & Mège, R.-M. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.98 · Cited by 749 · see citing works
Self-citation
- Authors
- Saw, T. B., Doostmohammadi, A., Nier, V., Kocgozlu, L., Thampi, S., Toyama, Y., Marcq, P., Lim, C. T., Yeomans, J. M., & Ladoux, B.
- Affiliations
- National University of Singapore (SG)
- University of Oxford (GB)
- Centre National de la Recherche Scientifique (FR)
- Indian Institute of Technology Madras (IN)
- Temasek Life Sciences Laboratory (SG)
- Corresponding author
- Lim, Chwee Teck
- Yeomans, Julia M.
- ORCID
- Venue
- Nature
- Published
- 2017-04-13
- Volume
- 544
- Issue
- 7649
- Pages
- 212-216
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5439518
- OpenAlex
- W2606063864
- Cited by
- 831
- References
- 63
- Citations by year
- 2026: 84 · 2025: 126 · 2024: 108 · 2023: 98 · 2022: 86 · 2021: 98 · 2020: 77 · 2019: 69 · 2018: 61 · 2017: 24
- FWCI
- 33.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Physical Sciences › Engineering › Mechanical Engineering › Advanced Materials and Mechanics
- Keywords
- topological defects, cell extrusion, cell death, epithelial mechanics, active nematic liquid crystals, cell orientation, mechanotransduction, YAP, caspase-3, cell-cell adhesion, alpha-catenin, microcontact printing, MDCK cells, compressive stress, apoptosis
- MeSH terms
- Animals, Cell Communication, Dogs, Epithelial Cells, Intercellular Junctions, Models, Biological, Transcription Factors, Cell Death, Apoptosis, Mechanotransduction, Cellular, Adaptor Proteins, Signal Transducing, Liquid Crystals, alpha Catenin, Caspase 3, Madin Darby Canine Kidney Cells
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