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Forces driving epithelial wound healing

Nature Physics volume 10, pages 683–690 (2014)Cite this article

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Abstract

A fundamental feature of multicellular organisms is their ability to self-repair wounds through the movement of epithelial cells into the damaged area. This collective cellular movement is commonly attributed to a combination of cell crawling and ‘purse-string’ contraction of a supracellular actomyosin ring. Here we show by direct experimental measurement that these two mechanisms are insufficient to explain force patterns observed during wound closure. At early stages of the process, leading actin protrusions generate traction forces that point away from the wound, showing that wound closure is initially driven by cell crawling. At later stages, we observed unanticipated patterns of traction forces pointing towards the wound. Such patterns have strong force components that are both radial and tangential to the wound. We show that these force components arise from tensions transmitted by a heterogeneous actomyosin ring to the underlying substrate through focal adhesions. The structural and mechanical organization reported here provides cells with a mechanism to close the wound by cooperatively compressing the underlying substrate.

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Figure 1: Cell morphology and kinematics during wound healing.
Figure 2: Traction forces during wound healing.
Figure 3: Traction forces in the absence of an actomyosin ring.
Figure 4: Traction forces after laser ablation of the actomyosin ring.
Figure 5: Force transmission from the ring to the substrate creates heterogeneous stresses and inward-pointing displacements of the underlying substrate.

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Acknowledgements

We thank M. Bintanel and F. Margadant for technical assistance and P. Roca-Cusachs and members of the Trepat laboratory for discussions. This research was supported by Fondation pour la Recherche Médicale (E.A.), the Spanish Ministry for Economy and Competitiveness (BFU2012-38146 to X.T., Juan de la Cierva Fellowship JCI-2012-15123 to V.C.), the European Research Council (Grant Agreement 242993, X.T.), the Agence Nationale de la Recherche (ANR 2010 BLAN 1515, B.L.), the Institut Universitaire de France (B.L.), the Human Frontier Science Program (grant RGP0040/2012, B.L.), the Mechanobiology Institute of Singapore (B.L.), and the Natural Sciences and Engineering Research Council of Canada (NSERC, J.H.V. and G.W.B.).

Author information

Author notes

  1. Agustí Brugués, Ester Anon and Vito Conte: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Bioengineering of Catalonia, Barcelona 08028, Spain

    Agustí Brugués, Ester Anon, Vito Conte & Xavier Trepat

  2. Institut Jacques Monod (IJM), Université Paris Diderot, and Unité Mixte de Recherche, 7592 CNRS Paris, France

    Ester Anon & Benoit Ladoux

  3. Department of Civil and Environmental Engineering, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada

    Jim H. Veldhuis & G. Wayne Brodland

  4. Mechanobiology Institute (MBI), National University of Singapore, Singapore 117411, Singapore

    Mukund Gupta & Benoit Ladoux

  5. Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain

    Julien Colombelli

  6. Department of Applied Mathematics III, Laboratori de Càlcul Numèric, Universitat Politècnica de Catalunya, 08036 Barcelona, Spain

    José J. Muñoz

  7. Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain

    Xavier Trepat

  8. Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, and CIBERES, 08036 Barcelona, Spain

    Xavier Trepat

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Contributions

A.B., E.A., J.C., B.L. and X.T. designed experiments; A.B. and E.A. performed experiments; A.B. analysed experimental data; A.B., V.C. and J.J.M. developed computational tools for data and stress analysis; M.G. analysed micropillar data; J.C. contributed technology; V.C., J.H.V. and G.W.B. built computational models and performed simulations; A.B., E.A., V.C., J.J.M., G.W.B., B.L. and X.T. wrote the manuscript; all authors discussed and interpreted results and commented on the manuscript; B.L. and X.T. conceived and supervised the project.

Corresponding authors

Correspondence to Benoit Ladoux or Xavier Trepat.

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The authors declare no competing financial interests.

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Brugués, A., Anon, E., Conte, V. et al. Forces driving epithelial wound healing. Nature Phys 10, 683–690 (2014). https://doi.org/10.1038/nphys3040

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