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Epithelial bridges maintain tissue integrity during collective cell migration

Nature Materials volume 13, pages 87–96 (2014)Cite this article

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Abstract

The ability of skin to act as a barrier is primarily determined by the efficiency of skin cells to maintain and restore its continuity and integrity. In fact, during wound healing keratinocytes migrate collectively to maintain their cohesion despite heterogeneities in the extracellular matrix. Here, we show that monolayers of human keratinocytes migrating along functionalized micropatterned surfaces comprising alternating strips of extracellular matrix (fibronectin) and non-adherent polymer form suspended multicellular bridges over the non-adherent areas. The bridges are held together by intercellular adhesion and are subjected to considerable tension, as indicated by the presence of prominent actin bundles. We also show that a model based on force propagation through an elastic material reproduces the main features of bridge maintenance and tension distribution. Our findings suggest that multicellular bridges maintain tissue integrity during wound healing when cell–substrate interactions are weak and may prove helpful in the design of artificial scaffolds for skin regeneration.

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Figure 1: Keratinocytes migrating on microcontact-printed fibronectin patterns form multicellular suspended epithelial bridges.
Figure 2: Migration dynamics of keratinocytes under different geometrical confinements.
Figure 3: Epithelial bridges are subjected to considerable tension.
Figure 4: Modelling epithelial-bridge formation as deformation of an elastic membrane.
Figure 5: Comparison of cell–cell rearrangements within HaCaT and MDCK monolayers using PIV.

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Acknowledgements

The authors thank C. Gay, J-B. Fournier, A. J. Kabla, R-M. Mège, J-M. di Meglio and W. James Nelson for helpful discussions. The authors would also like to thank M. Ashraf and S. Vaishnavi for the microfabrication and C. Xi for the illustrations. Financial support from the Agence Nationale de la Recherche (ANR 2010 BLAN 1515 awarded to B.L.), the Human Frontier Science Program (grant RGP0040/2012) and the Mechanobiology Institute (Team project funding) is gratefully acknowledged. B.L. acknowledges the Institut Universitaire de France (IUF) for its support. The research was conducted in the scope of the International Associated Laboratory Cell Adhesion France Singapore (CAFS). X.T. acknowledges financial support from the Spanish Ministry for Economy and Competitiveness (BFU2012-38146), and the European Research Council (Grant Agreement 242993).

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Author notes

  1. Sri Ram Krishna Vedula

    Present address: Present address: L’oreal Research and Innovation, #06-06, Neuros, 8A Biomedical Grove, 138648, Singapore,

Authors and Affiliations

  1. Mechanobiology Institute, National University of Singapore, 117411, Singapore

    Sri Ram Krishna Vedula, Hiroaki Hirata, Mui Hoon Nai, Yusuke Toyama, Chwee Teck Lim & Benoit Ladoux

  2. Institut de Bioenginyeria de Catalunya (IBEC), ICREA, and Facultat de Medicina—Universitat de Barcelona, 08028 Barcelona, Spain

    Agustı´ Brugués & Xavier Trepat

  3. Department of Biological Sciences, National University of Singapore and Temasek Life Sciences Laboratory, 117543, Singapore

    Yusuke Toyama

  4. Department of Biomedical Engineering and Department of Mechanical Engineering, National University of Singapore, 117576, Singapore

    Chwee Teck Lim

  5. Institut Jacques Monod (IJM), CNRS UMR 7592 and Université Paris Diderot, Paris 75013, France

    Benoit Ladoux

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Contributions

S.R.K.V., B.L. and C.T.L. designed research, S.R.K.V., M.H.N. and Y.T. performed experiments, H.H. contributed new reagents, S.R.K.V., A.B., H.H., X.T. and B.L. analysed data, S.R.K.V. and B.L. wrote the paper, and B.L. and C.T.L. oversaw the project. All authors read the manuscript and commented on it.

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Correspondence to Chwee Teck Lim or Benoit Ladoux.

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Vedula, S., Hirata, H., Nai, M. et al. Epithelial bridges maintain tissue integrity during collective cell migration. Nature Mater 13, 87–96 (2014). https://doi.org/10.1038/nmat3814

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