How cells with diverse morphologies and cytoskeletal architectures modulate their mechanical behaviours to drive robust collective motion within tissues is poorly understood. During wound repair within epithelial monolayers in vitro, cells coordinate the assembly of branched and bundled actin networks to regulate the total mechanical work produced by collective cell motion. Using traction force microscopy, we show that the balance of actin network architectures optimizes the wound closure rate and the magnitude of the mechanical work. These values are constrained by the effective power exerted by the monolayer, which is conserved and independent of actin architectures. Using a cell-based physical model, we show that the rate at which mechanical work is done by the monolayer is limited by the transformation between actin network architectures and differential regulation of cell–substrate friction. These results and our proposed mechanisms provide a robust physical model for how cells collectively coordinate their non-equilibrium behaviours to dynamically regulate tissue-scale mechanical output.

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Data availability

Data that support plots and other findings within this manuscript are available from the corresponding authors upon reasonable request.

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Custom codes that were used to analyse experimental data within this manuscript are available from the corresponding authors upon reasonable request.

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Journal peer review information: Nature Physics thanks Dimitrije Stamenovic and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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We acknowledge funding ARO MURI W911NF-14-1-0403 to M.P.M., D.R.K., C.S., V.A. and A.P.T. D.S.S. acknowledges support from National Science Foundation (NSF) Fellowship grant number DGE1122492. We acknowledge funding CMMI-1525316 and NIH RO1 GM126256 to M.P.M. and NIH U54 CA209992 to M.P.M. and M.S.Y. We also acknowledge fellowship support from the Yale Endowed Fund to V.A. M.F.S. is supported by a UK Engineering and Physical Sciences Research Council (EPSRC) PhD studentship at University College London (UCL). S.B. is supported by Royal Society Tata University Research Fellowship grant number URF/R1/180187, and acknowledges support from a Strategic Fellowship at UCL. S.B. and M.P.M. also acknowledge support from Human Frontiers Science Program (HFSP) grant number RGY0073/2018. Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors(s) and do not necessarily reflect the views of the NSF, NIH, HFSP, Royal Society, or EPSRC.

Author information

Author notes

  1. These authors contributed equally: Visar Ajeti, A. Pasha Tabatabai.


  1. Department of Biomedical Engineering, Yale University, New Haven, CT, USA

    • Visar Ajeti
    • , A. Pasha Tabatabai
    • , M. Sulaiman Yousafzai
    •  & Michael P. Murrell
  2. Systems Biology Institute, Yale University, West Haven, CT, USA

    • Visar Ajeti
    • , A. Pasha Tabatabai
    • , Daniel S. Seara
    • , M. Sulaiman Yousafzai
    •  & Michael P. Murrell
  3. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA

    • Andrew J. Fleszar
  4. Department of Physics and Astronomy, Institute for the Physics of Living Systems, University College London, London, UK

    • Michael F. Staddon
    •  & Shiladitya Banerjee
  5. Department of Physics, Yale University, New Haven, CT, USA

    • Daniel S. Seara
    •  & Michael P. Murrell
  6. Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL, USA

    • Cristian Suarez
    •  & David R. Kovar
  7. Department of Physics, Northeastern University, 111 Dana Research Center, Boston, MA, USA

    • Dapeng Bi


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M.P.M. designed and conceived the experimental work. S.B. designed and conceived the computational model. V.A., A.P.T., A.F. and M.S.Y. acquired experimental data. M.P.M., A.P.T., D.S.S., C.S. and V.A. analysed experimental data. M.F.S. implemented the model and performed simulations. D.B. provided computational tools and design. M.P.M. and S.B. contributed analytical tools. M.P.M., A.P.T., S.B., M.F.S. and D.K. wrote the paper. V.A. and A.P.T. are equal co-first authors, listed alphabetically, and A.J.F. and M.F.S. are equal co-second authors, listed alphabetically.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Michael P. Murrell.

Supplementary information

  1. Supplementary Information

    Supplementary Notes 1–4, Supplementary Equations, Supplementary Figures 1–10 and Supplementary References 1–10.

  2. Reporting Summary

  3. Supplementary Video 1

    Retraction of cell monolayer after ablation. DIC images of cell monolayer during wounding. Radial velocity vectors calculated from PIV measurements of DIC show a net outward flow, caused by a retraction of the monolayer. Scale bar is 20 μm.

  4. Supplementary Video 2

    Depolymerization of F-actin during monolayer retraction. Caco2 cell transiently transfected with LifeAct-GFP. Upon ablation, the cell retracts and forms both lamellipodial and purse string F-actin architectures. Concomitantly, cytoskeletal F-actin structures depolymerize. Scale bar is 25 μm.

  5. Supplementary Video 3

    Assembly of lamellipodia and purse string—early times. Ablation of epithelial sheets of Caco2 cells singly transfected with LifeAct-GFP. At the wound boundary, a cell assembles F-actin lamellipodium (left) and purse string (right) architectures. Scale bar is 20 μm.

  6. Supplementary Video 4

    Assembly of lamellipodia and purse string—late times. Ablation of epithelial sheets of Caco2 cells singly transfected with LifeAct-GFP. At the wound boundary, a cell assembles F-actin lamellipodial (left) and purse string (right) architectures. Scale bar is 20 μm.

  7. Supplementary Video 5

    Enhanced contrast of purse string during closure. Ablation of epithelial sheets of Caco2 cells singly transfected with LifeAct-GFP. At the wound boundary, a cell assembles an F-actin purse string architecture. Actin intensity is scaled to show details of the actin purse string. Scale bar is 20 μm.

  8. Supplementary Video 6

    Pharmacological controls. Wounds induced on 12.2 kPa substrates. CK666 and SMIFH2 inhibitors (left) and calcium–magnesium switch (right). Scale bar is 20 μm.

  9. Supplementary Video 7

    Wound closure for pharmacological perturbations. Wounds induced on 24 kPa substrates for the control (left), SMIFH2 (middle) and CK666 (right). Scale bar is 20 μm.

  10. Supplementary Video 8

    Pharmacological controls. Wounds induced on 12.2 kPa substrates. Nocodazole treatment to interfere with microtubule polymerization (left) and Y-27632 to biochemically inhibit ROCK1 and ROCK2 protein kinases (right). Scale bar is 20 μm.

  11. Supplementary Video 9

    Vertex model wound closure. Simulated wounds where the cells at the leading edge switch from lamellipodial crawling to purse string with a rate kPS. kPS = 1.5 h–1 (left) leads to primarily lamellipodial closure, whereas kPS = 3.5 h–1 (right) results in a complete transition to purse-string closure.

  12. Supplementary Video 10

    Instance of lamellipodial cell overcoming the leading purse string. Actin fluorescence images and traction stress maps for the rare case of a lamellipodial protrusion of a sub-marginal cell passing the purse string. Stresses localize to actin structures at wound edge. Scale bar is 20 μm.

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