Propulsion and navigation within the advancing monolayer sheet


As a wound heals, or a body plan forms, or a tumour invades, observed cellular motions within the advancing cell swarm are thought to stem from yet to be observed physical stresses that act in some direct and causal mechanical fashion. Here we show that such a relationship between motion and stress is far from direct. Using monolayer stress microscopy, we probed migration velocities, cellular tractions and intercellular stresses in an epithelial cell sheet advancing towards an island on which cells cannot adhere. We found that cells located near the island exert tractions that pull systematically towards this island regardless of whether the cells approach the island, migrate tangentially along its edge, or paradoxically, recede from it. This unanticipated cell-patterning motif, which we call kenotaxis, represents the robust and systematic mechanical drive of the cellular collective to fill unfilled space.

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Figure 1: Advancing monolayer of MDCK cells encounters and envelops a non-adherent island.
Figure 2: Orientations of tractions, velocities and principal stresses coincide, diverge and recover.
Figure 3: Cellular morphology, tight junction structure, and actin structure near the island.
Figure 4: Kenotactic tractions are evident in human mammary epithelial cells MCF10A vector, but are attenuated in MCF10A 14-3-3ζ, which disrupts adherens junctions.


  1. 1

    Rand, H. Wound closure in actinian tentacles with reference to the problem of organization. Rouxs Arch. Entwicklungsmech. Organismen 41, 159–214 (1915).

    Article  Google Scholar 

  2. 2

    Keller, R. Developmental biology. Physical biology returns to morphogenesis. Science 338, 201–203 (2012).

    CAS  Article  Google Scholar 

  3. 3

    Drasdo, D., Kree, R. & McCaskill, J. S. Monte Carlo approach to tissue–cell populations. Phys. Rev. E 52, 6635–6657 (1995).

    CAS  Article  Google Scholar 

  4. 4

    Farooqui, R. & Fenteany, G. Multiple rows of cells behind an epithelial wound edge extend cryptic lamellipodia to collectively drive cell-sheet movement. J. Cell Sci. 118, 51–63 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Hutson, M. S. et al. Forces for morphogenesis investigated with laser microsurgery and quantitative modeling. Science 300, 145–149 (2003).

    CAS  Article  Google Scholar 

  6. 6

    Kiehart, D. P., Galbraith, C. G., Edwards, K. A., Rickoll, W. L. & Montague, R. A. Multiple forces contribute to cell sheet morphogenesis for dorsal closure in Drosophila. J. Cell Biol. 149, 471–490 (2000).

    CAS  Article  Google Scholar 

  7. 7

    Saez, A. et al. Traction forces exerted by epithelial cell sheets. J. Phys. Condens. Matter 22, 194119 (2010).

    CAS  Article  Google Scholar 

  8. 8

    Reffay, M. et al. Orientation and polarity in collectively migrating cell structures: Statics and dynamics. Biophys. J. 100, 2566–2575 (2011).

    CAS  Article  Google Scholar 

  9. 9

    Tambe, D. T. et al. Collective cell guidance by cooperative intercellular forces. Nature Mater. 10, 469–475 (2011).

    CAS  Article  Google Scholar 

  10. 10

    Trepat, X. et al. Physical forces during collective cell migration. Nature Phys. 5, 426–430 (2009).

    CAS  Google Scholar 

  11. 11

    Tambe, D. T. et al. Monolayer stress microscopy: Limitations, artifacts, and accuracy of recovered intercellular stresses. PLoS One 8, e55172 (2013).

    CAS  Article  Google Scholar 

  12. 12

    Angelini, T. E. et al. Glass-like dynamics of collective cell migration. Proc. Natl Acad. Sci. USA 108, 4714–4719 (2011).

    CAS  Article  Google Scholar 

  13. 13

    Garrahan, J. P. Dynamic heterogeneity comes to life. Proc. Natl Acad. Sci. USA 108, 4701–4702 (2011).

    CAS  Article  Google Scholar 

  14. 14

    Serra-Picamal, X. et al. Mechanical waves during tissue expansion. Nature Phys. 8, 628–634 (2012).

    CAS  Article  Google Scholar 

  15. 15

    Trepat, X. & Fredberg, J. J. Plithotaxis and emergent dynamics in collective cellular migration. Trends Cell Biol. 21, 638–646 (2011).

    CAS  Article  Google Scholar 

  16. 16

    Weber, G. F., Bjerke, M. A. & DeSimone, D. W. A mechanoresponsive cadherin–keratin complex directs polarized protrusive behavior and collective cell migration. Dev. Cell 22, 104–115 (2012).

    CAS  Article  Google Scholar 

  17. 17

    Sadati, M., Qazvini, N. T., Krishnan, R., Park, C. Y. & Fredberg, J. J. Collective migration and cell jamming. Differentiation (in the press).

  18. 18

    Bindschadler, M. & McGrath, J. L. Sheet migration by wounded monolayers as an emergent property of single-cell dynamics. J. Cell Sci. 120, 876–884 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Basan, M., Elgeti, J., Hannezo, E., Rappel, W. & Levine, H. Alignment of cellular motility forces with tissue flow as a mechanism for efficient wound healing. Proc. Natl Acad. Sci. USA 110, 2452–2459 (2013).

    CAS  Article  Google Scholar 

  20. 20

    Matsubayashi, Y., Ebisuya, M., Honjoh, S. & Nishida, E. ERK activation propagates in epithelial cell sheets and regulates their migration during wound healing. Curr. Biol. 14, 731–735 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Block, E. R. et al. Free edges in epithelial cell sheets stimulate epidermal growth factor receptor signaling. Mol. Biol. Cell 21, 2172–2181 (2010).

    CAS  Article  Google Scholar 

  22. 22

    An, S. S. et al. Hypoxia alters biophysical properties of endothelial cells via p38 MAPK- and Rho kinase-dependent pathways. Am. J. Physiol. Cell Physiol. 289, C521–C530 (2005).

    CAS  Article  Google Scholar 

  23. 23

    Lu, J. et al. Breast cancer metastasis: Challenges and opportunities. Cancer Res. 69, 4951–4953 (2009).

    CAS  Article  Google Scholar 

  24. 24

    Mark, S. et al. Physical model of the dynamic instability in an expanding cell culture. Biophys. J. 98, 361–370 (2010).

    CAS  Article  Google Scholar 

  25. 25

    Wartlick, O. et al. Dynamics of Dpp signaling and proliferation control. Science 331, 1154–1159 (2011).

    CAS  Article  Google Scholar 

  26. 26

    Lauschke, V. M., Tsiairis, C. D., Francois, P. & Aulehla, A. Scaling of embryonic patterning based on phase-gradient encoding. Nature 493, 101–105 (2012).

    CAS  Article  Google Scholar 

  27. 27

    Morelli, L. G., Uriu, K., Ares, S. & Oates, A. C. Computational approaches to developmental patterning. Science 336, 187–191 (2012).

    CAS  Article  Google Scholar 

  28. 28

    Derby, B. Printing and prototyping of tissues and scaffolds. Science 338, 921–926 (2012).

    CAS  Article  Google Scholar 

  29. 29

    Soule, H. D. et al. Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res. 50, 6075–6086 (1990).

    CAS  Google Scholar 

  30. 30

    Poujade, M. et al. Collective migration of an epithelial monolayer in response to a model wound. Proc. Natl Acad. Sci. USA 104, 15988–15993 (2007).

    CAS  Article  Google Scholar 

  31. 31

    Butler, J. P., Tolic-Norrelykke, I. M., Fabry, B. & Fredberg, J. J. Traction fields, moments, and strain energy that cells exert on their surroundings. Am. J. Physiol. Cell Physiol. 282, C595–C605 (2002).

    CAS  Article  Google Scholar 

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We thank L. Kobzik and D. Tschumperlin (Harvard University) and J. H. T. Bates (University of Vermont) for their critical comments. We thank D. Yu (MDACC) for creating stable MCF10A cell lines and M. H. Zaman for providing us with them. This research was supported by the Spanish Ministry for Science and Innovation (BFU2012-38146 and FPU fellowship XS), the Swiss National Science Foundation (PBEZP2-140,047), the National Research Foundation of Korea (2012R1A6A3A03040450), the European Research Council (Grant Agreement 242,993), Parker B. Francis (Fellowship RK), American Heart Association (13SDG14320004) and the National Institutes of Health (R01HL102373, R01HL107561).

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J.H.K. designed cellular migration experiments. X.S-P. and B.G performed staining experiments. J.H.K, X.S-P., D.T.T., M.S., E.H.Z, C.Y.P. and B.G carried out migration experiments and data analysis. D.T.T. contributed software. C.Y.P, J-A.P. and R.K. contributed to protocol designs. E.M. contributed to data analysis. J.P.B. and J.J.F. guided data interpretation and analysis. J.H.K., J.P.B., X.T. and J.J.F. wrote the manuscript. J.J.F. oversaw the project.

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Correspondence to Jeffrey J. Fredberg.

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The authors declare no competing financial interests.

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Kim, J., Serra-Picamal, X., Tambe, D. et al. Propulsion and navigation within the advancing monolayer sheet. Nature Mater 12, 856–863 (2013).

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