The collective behaviour of cells in epithelial tissues is dependent on their mechanical properties. However, the contribution of tissue mechanics to wound healing in vivo remains poorly understood. Here, we investigate the relationship between tissue mechanics and wound healing in live Drosophila wing imaginal discs and show that by tuning epithelial cell junctional tension, we can systematically alter the rate of wound healing. Coincident with the contraction of an actomyosin purse string, we observe cells flowing past each other at the wound edge by intercalating, reminiscent of molecules in a fluid, resulting in seamless wound closure. Using a cell-based physical model, we predict that a reduction in junctional tension fluidizes the tissue through an increase in intercalation rate and corresponding reduction in bulk viscosity, in the manner of an unjamming transition. The resultant fluidization of the tissue accelerates wound healing. Accordingly, when we experimentally reduce tissue tension in wing discs, the intercalation rate increases and wounds repair in less time.
Subscribe to Journal
Get full journal access for 1 year
only $15.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
The code that supports the findings of this study are available from the corresponding author upon reasonable request.
Ladoux, B. & Mege, R. M. Mechanobiology of collective cell behaviours. Nat. Rev. Mol. Cell Biol. 18, 743–757 (2017).
Cochet-Escartin, O., Ranft, J., Silberzan, P. & Marcq, P. Border forces and friction control epithelial closure dynamics. Biophys. J. 106, 65–73 (2014).
Nier, V. et al. Tissue fusion over nonadhering surfaces. Proc. Natl Acad. Sci. USA 112, 9546–9551 (2015).
Arciero, J. C., Mi, Q., Branca, M. F., Hackam, D. J. & Swigon, D. Continuum model of collective cell migration in wound healing and colony expansion. Biophys. J. 100, 535–543 (2011).
Brugues, A. et al. Forces driving epithelial wound healing. Nat. Phys. 10, 683–690 (2014).
Vedula, S. R. K. et al. Mechanics of epithelial closure over non-adherent environments. Nat. Commun. 6, 6111 (2015).
Begnaud, S., Chen, T. C., Delacour, D., Mege, R. M. & Ladoux, B. Mechanics of epithelial tissues during gap closure. Curr. Opin. Cell Biol. 42, 52–62 (2016).
Russo, J. M. et al. Distinct temporal-spatial roles for Rho kinase and myosin light chain kinase in epithelial purse-string wound closure. Gastroenterology 128, 987–1001 (2005).
Abreu-Blanco, M. T., Verboon, J. M., Liu, R., Watts, J. J. & Parkhurst, S. M. Drosophila embryos close epithelial wounds using a combination of cellular protrusions and an actomyosin purse string. J. Cell Sci. 125, 5984–5997 (2012).
Wood, W. et al. Wound healing recapitulates morphogenesis in Drosophila embryos. Nat. Cell Biol. 4, 907–912 (2002).
Brock, J., Midwinter, K., Lewis, J. & Martin, P. Healing of incisional wounds in the embryonic chick wing bud: characterization of the actin purse-string and demonstration of a requirement for Rho activation. J. Cell Biol. 135, 1097–1107 (1996).
Davidson, L. A., Ezin, A. M. & Keller, R. Embryonic wound healing by apical contraction and ingression in Xenopus laevis. Cell Motil. Cytoskeleton 53, 163–176 (2002).
Zulueta-Coarasa, T. & Fernandez-Gonzalez, R. Dynamic force patterns promote collective cell movements during embryonic wound repair. Nat. Phys. 14, 750–758 (2018).
Kobb, A. B., Zulueta-Coarasa, T. & Fernandez-Gonzalez, R. Tension regulates myosin dynamics during Drosophila embryonic wound repair. J. Cell Sci. 130, 689–696 (2017).
Bement, W. M., Forscher, P. & Mooseker, M. S. A novel cytoskeletal structure involved in purse string wound closure and cell polarity maintenance. J. Cell Biol. 121, 565–578 (1993).
Martin, P. & Lewis, J. Actin Cables and epidermal movement in embryonic wound-healing. Nature 360, 179–183 (1992).
Bement, W. M., Mandato, C. A. & Kirsch, M. N. Wound-induced assembly and closure of an actomyosin purse string in Xenopus oocytes. Curr. Biol. 9, 579–587 (1999).
Danjo, Y. & Gipson, I. K. Actin ‘purse string’ filaments are anchored by E-cadherin-mediated adherens junctions at the leading edge of the epithelial wound, providing coordinated cell movement. J. Cell Sci. 111, 3323–3332 (1998).
Heller, D. et al. EpiTools: an open-source image analysis toolkit for quantifying epithelial growth dynamics. Dev. Cell 36, 103–116 (2016).
Galko, M. J. & Krasnow, M. A. Cellular and genetic analysis of wound healing in Drosophila larvae. PLoS Biol. 2, 1114–1126 (2004).
Losick, V. P., Fox, D. T. & Spradling, A. C. Polyploidization and cell fusion contribute to wound healing in the adult Drosophila epithelium. Curr. Biol. 23, 2224–2232 (2013).
Razzell, W., Wood, W. & Martin, P. Recapitulation of morphogenetic cell shape changes enables wound re-epithelialisation. Development 141, 1814–1820 (2014).
Tetley, R. J. & Mao, Y. The same but different: cell intercalation as a driver of tissue deformation and fluidity. Phil. Trans. R. Soc. Lond. B Biol. Sci. 373, 20170328 (2018).
Fletcher, A. G., Osterfield, M., Baker, R. E. & Shvartsman, S. Y. Vertex models of epithelial morphogenesis. Biophys. J. 106, 2291–2304 (2014).
Wyczalkowski, M. A., Varner, V. D. & Taber, L. A. Computational and experimental study of the mechanics of embryonic wound healing. J. Mech. Behav. Biomed. 28, 125–146 (2013).
Barton, D. L., Henkes, S., Weijer, C. J. & Sknepnek, R. Active vertex model for cell-resolution description of epithelial tissue mechanics. PLoS Comput. Biol. 13, e1005569 (2017).
Staddon, M. F. et al. Cooperation of dual modes of cell motility promotes epithelial stress relaxation to accelerate wound healing. PLoS Comput. Biol. 14, e1006502 (2018).
Curran, S. et al. Myosin II controls junction fluctuations to guide epithelial tissue ordering. Dev. Cell 43, 480–492 (2017).
Shindo, A. et al. Septin-dependent remodeling of cortical microtubule drives cell reshaping during epithelial wound healing. J. Cell Sci. 131, 212647 (2018).
Anon, E. et al. Cell crawling mediates collective cell migration to close undamaged epithelial gaps. Proc. Natl Acad. Sci. USA 109, 10891–10896 (2012).
Bi, D. P., Lopez, J. H., Schwarz, J. M. & Manning, M. L. A density-independent rigidity transition in biological tissues. Nat. Phys. 11, 1074–1079 (2015).
Vedula, S. R. et al. Epithelial bridges maintain tissue integrity during collective cell migration. Nat. Mater. 13, 87–96 (2014).
Bergantinos, C., Corominas, M. & Serras, F. Cell death-induced regeneration in wing imaginal discs requires JNK signalling. Development 137, 1169–1179 (2010).
Vereshchagina, N. et al. The essential role of PP1 beta in Drosophila is to regulate nonmuscle myosin. Mol. Biol. Cell 15, 4395–4405 (2004).
Amano, M. et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J. Biol. Chem. 271, 20246–20249 (1996).
Mizuno, T., Amano, M., Kaibuchi, K. & Nishida, Y. Identification and characterization of Drosophila homolog of Rho-kinase. Gene 238, 437–444 (1999).
Lecuit, T. & Lenne, P. F. Cell surface mechanics and the control of cell shape, tissue patterns and morphogenesis. Nat. Rev. Mol. Cell Biol. 8, 633–644 (2007).
Verboon, J. M. & Parkhurst, S. M. Rho family GTPase functions in Drosophila epithelial wound repair. Small GTPases 6, 28–35 (2015).
Farhadifar, R., Roper, J. C., Algouy, B., Eaton, S. & Julicher, F. The influence of cell mechanics, cell–cell interactions, and proliferation on epithelial packing. Curr. Biol. 17, 2095–2104 (2007).
Chepizhko, O. et al. From jamming to collective cell migration through a boundary induced transition. Soft Matter 14, 3774–3782 (2018).
Brugues, A. et al. Forces driving epithelial wound healing. Nat. Phys. 10, 684–691 (2014).
Fenteany, G., Janmey, P. A. & Stossel, T. P. Signaling pathways and cell mechanics involved in wound closure by epithelial cell sheets. Curr. Biol. 10, 831–838 (2000).
Park, J. A., Atia, L., Mitchel, J. A., Fredberg, J. J. & Butler, J. P. Collective migration and cell jamming in asthma, cancer and development. J. Cell Sci. 129, 3375–3383 (2016).
Sadati, M., Qazvini, N. T., Krishnan, R., Park, C. Y. & Fredberg, J. J. Collective migration and cell jamming. Differentiation 86, 121–125 (2013).
Liu, A. J. & Nagel, S. R. Nonlinear dynamics—jamming is not just cool any more. Nature 396, 21–22 (1998).
Park, J. A. et al. Unjamming and cell shape in the asthmatic airway epithelium. Nat. Mater. 14, 1040–1048 (2015).
Miroshnikova, Y. A. et al. Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification. Nat. Cell Biol. 20, 69–80 (2018).
Firmino, J., Rocancourt, D., Saadaoui, M., Moreau, C. & Gros, J. Cell division drives epithelial cell rearrangements during gastrulation in chick. Dev. Cell 36, 249–261 (2016).
Petridou, N. I., Grigolon, S., Salbreux, G., Hannezo, E. & Heisenberg, C. P. Fluidization-mediated tissue spreading by mitotic cell rounding and non-canonical Wnt signalling. Nat. Cell Biol. 21, 169–178 (2019).
Mongera, A. et al. A fluid-to-solid jamming transition underlies vertebrate body axis elongation. Nature 561, 401–405 (2018).
R.J.T. was funded by a Medical Research Council Skills Development Fellowship (MR/N014529/1). M.F.S. is supported by an EPSRC funded PhD Studentship at the UCL Department of Physics and Astronomy. D.H. was supported by the Swiss National Science Foundation (31003A-160095). S.B. acknowledges support from Royal Society University Research Fellowship (URF/R1/180187), and a Strategic Fellowship from the UCL Institute for the Physics of Living Systems. Y.M. is funded by a Medical Research Council Fellowship (MR/L009056/1), a UCL Excellence Fellowship, a NSFC International Young Scientist Fellowship (31650110472) and a Lister Institute Research Prize Fellowship. This work was also supported by MRC funding to the MRC LMCB University Unit at UCL (award code MC_U12266B). We thank all members of the Mao group, M. Raff, D. Ish-Horowicz and M. Murrell for providing feedback on the manuscript. We also thank the Baum and Tapon laboratories for sharing fly stocks.
The authors declare no competing interests.
Peer review information: Nature Physics thanks Marino Arroyo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Methods, Supplementary Figs. 1–10, Table 1 and Videos 1–7.
Myosin II localization during Drosophila wing-disc wound closure.
Wild-type wound closure.
Vertex-model simulation of wound healing with intercalations disabled.
Vertex-model simulation of wound healing with intercalations enabled.
Analysing the first three rows of cells away from the wound.
Wound closure in an Mbs RNAi wing disc.
Wound closure in a Rok RNAi wing disc.
About this article
Cite this article
Tetley, R.J., Staddon, M.F., Heller, D. et al. Tissue fluidity promotes epithelial wound healing. Nat. Phys. 15, 1195–1203 (2019). https://doi.org/10.1038/s41567-019-0618-1
Physical Review X (2020)
Soft Matter (2020)
Frontiers in Bioengineering and Biotechnology (2020)
Biochemical and Biophysical Research Communications (2020)
Developmental Cell (2020)