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The role of transcription-independent damage signals in the initiation of epithelial wound healing

Nature Reviews Molecular Cell Biology volume 14, pages 249–262 (2013)Cite this article

Subjects

Key Points

  • Wound healing is an essential and complex biological process comprising a series of steps, including cell shape changes and rearrangements as well as immune cell recruitment and activation, aimed at restoring tissue function and integrity following injury. Embryonic wound healing differs from adult wound healing by being less complicated, more efficient and not leading to the formation of scar tissue.

  • Immediately after sustaining injury, cells generate conserved molecular signals that diffuse within tissues to alert and promote immediate gene transcription-independent wound healing responses. These signals include Ca2+, H2O2 and ATP.

  • Ca2+ waves form in injured tissues of vertebrate and invertebrate origin within seconds of damage and disappear minutes after. Increased intracellular Ca2+ levels following injury result from Ca2+ internalization through transient receptor potential (TRP) channels and release from internal stores. Increased Ca2+ promotes changes in the actin cytoskeleton through RHO GTPase-mediated regulation.

  • Injury causes rapid formation of H2O2 gradients that involves the action of the NADPH oxidase DUOX. H2O2 is an immune cell chemoattractant in vertebrate and invertebrate organisms and is an essential promoter of the wound healing inflammatory response.

  • As a result of damage, ATP is released from cells and taken up by neighbouring cells through purinergic receptors. ATP forms a chemical gradient in these cells that is sensed by immune cells and leads to their recruitment to the site of injury.

  • Transcription-independent diffusible damage signals crosstalk with each other, and their mechanisms of action are highly integrated. For example, ATP and Ca2+ regulate DUOX activity and consequent H2O2 formation, Ca2+ promotes ATP exocytosis, and ATP and Ca2+ are co-internalized by purinergic receptors.

  • Transcription-independent damage signals subsequently affect transcription of wound response genes either directly or indirectly by regulating receptor Tyr kinases and ERK or JNK signalling. They thereby promote the activation of transcription factors such as grainy head, FOS and JUN.

  • Transcription-independent diffusible damage signals are formed in cells as a result of mechanosensing mechanisms, involving cell–cell adhesions and the actin cytoskeleton, as well as redox and temperature changes that can cause membrane channel opening as a result of injury.

  • Immediate wound healing processes that are determined by transcription-independent diffusible damage signals affect later events and influence wound healing outcomes. The choice of preferred epithelial resealing mechanism and late fibrin and collagen deposition resulting from inflammation are two examples of late processes that are influenced by early signalling events.

Abstract

Wound healing is an essential biological process that comprises sequential steps aimed at restoring the architecture and function of damaged cells and tissues. This process begins with conserved damage signals, such as Ca2+, hydrogen peroxide (H2O2) and ATP, that diffuse through epithelial tissues and initiate immediate gene transcription-independent cellular effects, including cell shape changes, the formation of functional actomyosin structures and the recruitment of immune cells. These events integrate the ensuing transcription of specific wound response genes that further advance the wound healing response. The immediate importance of transcription-independent damage signals illustrates that healing a wound begins as soon as damage occurs.

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Figure 1: Damage signalling pathways and damage message integration.
Figure 2: Damage message progress and effects during early wound healing.

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References

  1. Sonnemann, K. J. & Bement, W. M. Wound repair: toward understanding and integration of single-cell and multicellular wound responses. Annu. Rev. Cell Dev. Biol. 27, 237–263 (2011). Offers a comprehensive review of the wound healing process and the main wound healing mechanisms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Furie, B. & Furie, B. C. Mechanisms of thrombus formation. N. Engl. J. Med. 359, 938–949 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 453, 314–321 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Thorgeirsson, S. S. & Grisham, J. W. Molecular pathogenesis of human hepatocellular carcinoma. Nature Genet. 31, 339–346 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Walter, N. D. et al. Wound healing after trauma may predispose to lung cancer metastasis: review of potential mechanisms. Am. J. Respir. Cell Mol. Biol. 44, 591–596 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Trent, J. T. & Kirsner, R. S. Wounds and malignancy. Adv. Skin Wound Care 16, 31–34 (2003).

    Article  PubMed  Google Scholar 

  7. Shanmugam, V., DeMaria, D. & Attinger, C. Lower extremity ulcers in rheumatoid arthritis: features and response to immunosuppression. Clin. Rheumatol. 30, 849–853 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Arwert, E. N., Hoste, E. & Watt, F. M. Epithelial stem cells, wound healing and cancer. Nature Rev. Cancer 12, 170–180 (2012).

    Article  CAS  Google Scholar 

  9. Grice, E. A. & Segre, J. A. The skin microbiome. Nature Rev. Microbiol. 9, 244–253 (2011).

    Article  CAS  Google Scholar 

  10. Frank, D. N. et al. Microbial diversity in chronic open wounds. Wound Repair Regen. 17, 163–172 (2009).

    Article  PubMed  Google Scholar 

  11. Wood, W. et al. Wound healing recapitulates morphogenesis in Drosophila embryos. Nature Cell Biol. 4, 907–912 (2002). Describes the cell shape changes and rearrangements that occur during epithelial resealing and highlights the importance of conserved cytoskeleton regulators for proper wound healing.

    Article  CAS  PubMed  Google Scholar 

  12. Galko, M. J. & Krasnow, M. A. Cellular and genetic analysis of wound healing in Drosophila larvae. PLoS Biol. 2, e239 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Grose, R. & Werner, S. Wound-healing studies in transgenic and knockout mice. Mol. Biotechnol. 28, 147–166 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Dvorak, H. F. Tumors: wounds that do not heal. N. Engl. J. Med. 315, 1650–1659 (1986). A classic paper that discusses the evidence that wound healing and cancer have significant similarities and proposes the provocative hypothesis that tumours behave as wounds that do not heal.

    Article  CAS  PubMed  Google Scholar 

  15. Schäfer, M. & Werner, S. Cancer as an overhealing wound: an old hypothesis revisited. Nature Rev. Mol. Cell Biol. 9, 628–638 (2008). Describes the parallels between wound healing and cancer and revisits the classic model presented in reference 14 that views tumours as wounds that do not heal.

    Article  CAS  Google Scholar 

  16. Gonda, T. A., Tu, S. & Wang, T. C. Chronic inflammation, the tumor microenvironment and carcinogenesis. Cell Cycle 8, 2005–2013 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Shaw, T. J. & Martin, P. Wound repair at a glance. J. Cell Sci. 122, 3209–3213 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Singer, A. J. & Clark, R. A. Cutaneous wound healing. N. Engl. J. Med. 341, 738–746 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Kenchegowda, S. & Bazan, H. E. P. Significance of lipid mediators in corneal injury and repair. J. Lipid Res. 51, 879–891 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Trabold, O. et al. Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Wound Repair Regen. 11, 504–509 (2003).

    Article  PubMed  Google Scholar 

  21. Sen, C. K. Wound healing essentials: let there be oxygen. Wound Repair Regen. 17, 1–18 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Müller, A.-K., Meyer, M. & Werner, S. The roles of receptor tyrosine kinases and their ligands in the wound repair process. Semin. Cell Dev. Biol. 23, 963–970 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Garcia-Fernandez, B., Campos, I., Geiger, J., Santos, A. C. & Jacinto, A. Epithelial resealing. Int. J. Dev. Biol. 53, 1549–1556 (2009).

    Article  PubMed  Google Scholar 

  24. Werner, S. & Grose, R. Regulation of wound healing by growth factors and cytokines. Physiol. Rev. 83, 835–870 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Martin, P. Wound healing — aiming for perfect skin regeneration. Science 276, 75–81 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    CAS  PubMed  Google Scholar 

  27. Martin, P. & Lewis, J. Actin cables and epidermal movement in embryonic wound healing. Nature 360, 179–183 (1992).

    Article  CAS  PubMed  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jacinto, A., Martinez-Arias, A. & Martin, P. Mechanisms of epithelial fusion and repair. Nature Cell Biol. 3, e117–e123 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Bullen, T. F. et al. Characterization of epithelial cell shedding from human small intestine. Lab. Invest. 86, 1052–1063 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

  35. Rosenblatt, J., Raff, M. C. & Cramer, L. P. An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr. Biol. 11, 1847–1857 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Slattum, G., McGee, K. M. & Rosenblatt, J. P115 RhoGEF and microtubules decide the direction apoptotic cells extrude from an epithelium. J. Cell Biol. 186, 693–702 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Babcock, D. T. et al. Circulating blood cells function as a surveillance system for damaged tissue in Drosophila larvae. Proc. Natl Acad. Sci. USA 105, 10017–10022 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Wood, W., Faria, C., & Jacinto A. Distinct mechanisms regulate hemocyte chemotaxis during development and wound healing in Drosophila melanogaster. J. Cell Biol. 173, 405–416 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Moreira, S., Stramer, B., Evans, I., Wood, W. & Martin, P. Prioritization of competing damage and developmental signals by migrating macrophages in the Drosophila embryo. Curr. Biol. 20, 464–470 (2010). Identifies H 2 O 2 as an immediate damage signal that attracts immune cells to wounds in D. melanogaster embryos and describes the capacity of these cells to distinguish between competing signals.

    Article  CAS  PubMed  Google Scholar 

  40. Martin, P. & Leibovich, S. J. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 15, 599–607 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Martin, P. et al. Wound healing in the PU.1 null mouse — tissue repair is not dependent on inflammatory cells. Curr. Biol. 13, 1122–1128 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Eming, S. A., Krieg, T. & Davidson, J. M. Inflammation in wound repair: molecular and cellular mechanisms. J. Invest. Dermatol. 127, 514–525 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Stramer, B. M., Mori, R. & Martin, P. The inflammation–fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J. Invest. Dermatol. 127, 1009–1017 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Campos, I., Geiger, J. A., Santos, A. C., Carlos, V. & Jacinto, A. Genetic screen in Drosophila melanogaster uncovers a novel set of genes required for embryonic epithelial repair. Genetics 184, 129–140 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang, S. et al. The tyrosine kinase Stitcher activates Grainy head and epidermal wound healing in Drosophila. Nature Cell Biol. 11, 890–895 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Wu, Y. et al. A blood-borne PDGF/VEGF-like ligand initiates wound-induced epidermal cell migration in Drosophila larvae. Curr. Biol. 19, 1473–1477 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rämet, M., Lanot, R., Zachary, D. & Manfruelli, P. J.N. K. Signaling pathway is required for efficient wound healing in Drosophila. Dev. Biol. 241, 145–156 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Bosch, M., Serras, F., Martín-Blanco, E. & Baguñà, J. JNK signaling pathway required for wound healing in regenerating Drosophila wing imaginal discs. Dev. Biol. 280, 73–86 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Clark, A. G. et al. Integration of single and multicellular wound responses. Curr. Biol. 19, 1389–1395 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Joshi, S. D., Dassow, von, M. & Davidson, L. A. Experimental control of excitable embryonic tissues: three stimuli induce rapid epithelial contraction. Exp. Cell Res. 316, 103–114 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Xu, S. & Chisholm, A. D. A Gαq–Ca2+ signaling pathway promotes actin-mediated epidermal wound closure in C. elegans. Curr. Biol. 21, 1960–1967 (2011). Identifies Ca2+ as an immediate damage signal in C. elegans skin wound healing and describes a molecular mechanism that has a significant role in the formation of actin structures following damage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Niethammer, P., Grabher, C., Look, A. T. & Mitchison, T. J. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 459, 996–999 (2009). Provides compelling in vivo evidence of the formation of tissue-wide H 2 O 2 gradients following damage to zebrafish larvae.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yoo, S. K., Freisinger, C. M., LeBert, D. C. & Huttenlocher, A. Early redox Src family kinase, and calcium signaling integrate wound responses and tissue regeneration in zebrafish. J. Cell Biol. 199, 225–234 (2012). Shows the importance of Ca2+ as an immediate damage signal following injury to zebrafish larvae and confirms the formation of H 2 O 2 gradients as relevant immediate damage signals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Maeda, M., Tsuda, M., Tozaki-Saitoh, H., Inoue, K. & Kiyama, H. Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn. Glia 58, 1838–1846 (2010).

    Article  PubMed  Google Scholar 

  55. Love, N. R. et al. Amputation-induced reactive oxygen species are required for successful Xenopus tadpole tail regeneration. Nature Cell Biol. 13 Jan 2013 (doi:10.1038/ncb2659).

  56. Clapham, D. E. Calcium signaling. Cell 131, 1047–1058 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Stanisstreet, M. Calcium and wound healing in Xenopus early embryos. J. Embryol. Exp. Morphol. 67, 195–205 (1982).

    CAS  PubMed  Google Scholar 

  58. McNeil, P. L. & Steinhardt, R. A. Plasma membrane disruption: repair, prevention, adaptation. Annu. Rev. Cell Dev. Biol. 19, 697–731 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Tran, P. O., Hinman, L. E., Unger, G. M. & Sammak, P. J. A wound-induced [Ca2+]i increase and its transcriptional activation of immediate early genes is important in the regulation of motility. Exp. Cell Res. 246, 319–326 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Lansdown, A. B. G. Calcium: a potential central regulator in wound healing in the skin. Wound Repair Regen. 10, 271–285 (2002).

    Article  PubMed  Google Scholar 

  61. Kawai, K. et al. Calcium-based nanoparticles accelerate skin wound healing. PLoS ONE 6, e27106 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sammak, P. J., Hinman, L. E., Tran, P. O., Sjaastad, M. D. & Machen, T. E. How do injured cells communicate with the surviving cell monolayer? J. Cell Sci. 110, 465–475 (1997).

    CAS  PubMed  Google Scholar 

  63. Klepeis, V. E., Cornell-Bell, A. & Trinkaus-Randall, V. Growth factors but not gap junctions play a role in injury-induced Ca2+ waves in epithelial cells. J. Cell Sci. 114, 4185–4195 (2001).

    CAS  PubMed  Google Scholar 

  64. Chifflet, S. et al. Early and late calcium waves during wound healing in corneal endothelial cells. Wound Repair Regen. 20, 28–37 (2011).

    Article  PubMed  Google Scholar 

  65. Chifflet, S. Hernández, J. A., Grasso, S. & Cirillo, A. Nonspecific depolarization of the plasma membrane potential induces cytoskeletal modifications of bovine corneal endothelial cells in culture. Exp. Cell Res. 282, 1–13 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Gale, J. E., Piazza, V., Ciubotaru, C. D. & Mammano, F. A. Mechanism for sensing noise damage in the inner ear. Curr. Biol. 14, 526–529 (2004). A pioneering study using whole organ cultures of rat cochlea that shows the role of intercellular Ca2+ waves in response to noise-induced damage.

    Article  CAS  PubMed  Google Scholar 

  67. Wood, W. Wound healing: calcium flashes illuminate early events. Curr. Biol. 22, R14–R16 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Tian, L. et al. Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators. Nature Methods 6, 875–881 (2009). Reports important technical advances in the use of genetically encoded Ca2+ indicators to image and quantify intracellular Ca2+ levels in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Benink, H. A. & Bement, W. M. Concentric zones of active RhoA and Cdc42 around single cell wounds. J. Cell Biol. 168, 429–439 (2005). Describes concentric regions of differential RHO GTPase activation that coincide with regions of high Ca2+ levels around wounds in X. laevis eggs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Jaffe, A. B. & Hall, A. Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21, 247–269 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Ghannad-Rezaie, M., Wang, X., Mishra, B., Collins, C. & Chronis, N. Microfluidic chips for in vivo imaging of cellular responses to neural injury in Drosophila larvae. PLoS ONE 7, e29869 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine (Oxford Univ. Press, 2007).

  73. Dickinson, B. C. & Chang, C. J. Chemistry and biology of reactive oxygen species in signaling or stress responses. Nature Chem. Biol. 7, 504–511 (2011).

    Article  CAS  Google Scholar 

  74. Goitre, L., Pergolizzi, B., Ferro, E., Trabalzini, L. & Retta, S. F. Molecular crosstalk between integrins and cadherins: do reactive oxygen species set the talk? J. Signal Transduct. 2012, 1–12 (2012).

    Article  CAS  Google Scholar 

  75. Hurd, T. R., DeGennaro, M. & Lehmann, R. Redox regulation of cell migration and adhesion. Trends Cell Biol. 22, 107–115 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Reth, M. Hydrogen peroxide as second messenger in lymphocyte activation. Nature Immunol. 3, 1129–1134 (2002).

    Article  CAS  Google Scholar 

  77. Sen, C. K. & Roy, S. Redox signals in wound healing. Biochim. Biophys. Acta 1780, 1348–1361 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Veal, E. A., Day, A. M. & Morgan, B. A. Hydrogen peroxide sensing and signaling. Mol. Cell 26, 1–14 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Bienert, G. P., Schjoerring, J. K. & Jahn, T. P. Membrane transport of hydrogen peroxide. Biochim. Biophys. Acta 1758, 994–1003 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Bollinger, J. M. Jr Biochemistry: electron relay in proteins. Science 320, 1730–1731 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Klyubin, I. V. I., Kirpichnikova, K. M. K. & Gamaley, I. A. I. Hydrogen peroxide-induced chemotaxis of mouse peritoneal neutrophils. Eur. J. Cell Biol. 70, 347–351 (1996).

    CAS  PubMed  Google Scholar 

  82. Li, W., Liu, G., Chou, I. N. & Kagan, H. M. Hydrogen peroxide-mediated, lysyl oxidase-dependent chemotaxis of vascular smooth muscle cells. J. Cell. Biochem. 78, 550–557 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Belousov, V. V. et al. Genetically encoded fluorescent indicator for intracellular hydrogen peroxide. Nature Methods 3, 281–286 (2006). Reports the development of a genetically encoded H 2 O 2 fluorescent indicator to image and quantify intracellular H 2 O 2 levels in vivo.

    Article  CAS  PubMed  Google Scholar 

  84. Rhee, S. G., Chang, T.-S., Jeong, W. & Kang, D. Methods for detection and measurement of hydrogen peroxide inside and outside of cells. Mol. Cells 29, 539–549 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Kawahara, B., Quinn, M. T. & Lambeth, J. D. Molecular evolution of the reactive oxygen-generating NADPH oxidase (Nox/Duox) family of enzymes. BMC Evol. Biol. 7, 109 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rieger, S. & Sagasti, A. Hydrogen peroxide promotes injury-induced peripheral sensory axon regeneration in the zebrafish skin. PLoS Biol. 9, e1000621 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Peri, F. Breaking ranks: how leukocytes react to developmental cues and tissue injury. Curr. Opin. Genet. Dev. 20, 416–419 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Yoo, S. K. & Huttenlocher, A. Innate immunity: wounds burst H2O2 signals to leukocytes. Curr. Biol. 19, R553–R555 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Feng, Y., Santoriello, C., Mione, M., Hurlstone, A. & Martin, P. Live imaging of innate immune cell sensing of transformed cells in zebrafish larvae: parallels between tumor initiation and wound inflammation. Plos Biol. 8, e1000562 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Pastor-Pareja, J. C., Wu, M. & Xu, T. An innate immune response of blood cells to tumors and tissue damage in Drosophila. Dis. Model. Mech. 1, 144–154 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  91. la Sala, A. et al. Alerting and tuning the immune response by extracellular nucleotides. J. Leukoc. Biol. 73, 339–343 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Di Virgilio, F. et al. Nucleotide receptors: an emerging family of regulatory molecules in blood cells. Blood 97, 587–600 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Idzko, M. et al. Nucleotides induce chemotaxis and actin polymerization in immature but not mature human dendritic cells via activation of pertussis toxin-sensitive P2y receptors. Blood 100, 925–932 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Yin, J., Xu, K., Zhang, J., Kumar, A. & Yu, F. S. X. Wound-induced ATP release and EGF receptor activation in epithelial cells. J. Cell Sci. 120, 815–825 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Baroja-Mazo, A., Barberà-Cremades, M. & Pelegrín, P. The participation of plasma membrane hemichannels to purinergic signaling. Biochim. Biophys. Acta 1828, 79–93 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nature Neurosci. 8, 752–758 (2005). An important study reporting immediate ATP release as a result of damage to astrocytes and the role of ATP as a microglia attractant in the response to injury.

    Article  CAS  PubMed  Google Scholar 

  97. Anderson, C. M., Bergher, J. P. & Swanson, R. A. ATP-induced ATP release from astrocytes. J. Neurochem. 88, 246–256 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Stout, C. E., Costantin, J., L., Naus, C. C. & Charles, A. C. Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J. Biol. Chem. 277, 10482–10488 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Corriden, R. & Insel, P. A. Basal release of ATP: an autocrine-paracrine mechanism for cell regulation. Sci. Signal. 3, re1 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Abbracchio, M. P., Burnstock, G., Verkhratsky, A. & Zimmermann, H. Purinergic signalling in the nervous system: an overview. Trends Neurosci. 32, 19–29 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Honda, S. et al. Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J. Neurosci. 21, 1975–1982 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ciccarelli, R. et al. Involvement of astrocytes in purine-mediated reparative processes in the brain. Int. J. Dev. Neurosci. 19, 395–414 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Burnstock, G., Knight, G. E. & Greig, A. V. H. Purinergic signaling in healthy and diseased skin. J. Invest. Dermatol. 132, 526–546 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Seong, S.-Y. & Matzinger, P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nature Rev. Immunol. 4, 469–478 (2004).

    Article  CAS  Google Scholar 

  105. Kono, H. & Rock, K. L. How dying cells alert the immune system to danger. Nature Rev. Immunol. 8, 279–289 (2008).

    Article  CAS  Google Scholar 

  106. Bianchi, M. E. DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukocyte Biol. 81, 1–5 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Ahrens, S. et al. F-Actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 36, 635–645 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Burns, S. & Thrasher, A. J. Dendritic cells: the bare bones of immunity. Curr. Biol. 14, R965–R967 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Hudson, B. I. et al. Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J. Biol. Chem. 283, 34457–34468 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ryckman, C., Vandal, K., Rouleau, P., Talbot, M. & Tessier, P. A. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J. Immunol. 170, 3233–3242 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Hirst, D. G. & Robson, T. Nitric oxide physiology and pathology. Methods Mol. Biol. 704, 1–13 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Luo, J.-D. & Chen, A. F. Nitric oxide: a newly discovered function on wound healing. Acta Pharmacol. Sin. 26, 259–264 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Durbin, A., Nadir, N.-A., Rosenthal, A. & Gotlieb, A. I. Nitric oxide promotes in vitro interstitial cell heart valve repair. Cardiovasc. Pathol. 14, 12–18 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Witte, M. B. & Barbul, A. Role of nitric oxide in wound repair. Am. J. Surg. 183, 406–412 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Yamasaki, K. et al. Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J. Clin. Invest. 101, 967–971 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Luo, J.-D., Wang, Y. Y., Fu, W. L., Wu, J. & Chen A. F. Gene therapy of endothelial nitric oxide synthase and manganese superoxide dismutase restores delayed wound healing in type 1 diabetic mice. Circulation 110, 2484–2493 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Zhang, R. et al. Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ. Res. 92, 308–313 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Dhaunsi, G. S. & Ozand, P. T. Nitric oxide promotes mitogen-induced DNA synthesis in human dermal fibroblasts through cGMP. Clin. Exp. Pharmacol. Physiol. 31, 46–49 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Sparkman, L. & Boggaram, V. Nitric oxide increases IL-8 gene transcription and mRNA stability to enhance IL-8 gene expression in lung epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L764–L773 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Malik, A. A., Radhakrishnan, N., Reddy, K., Smith, A. D. & Singhal, P. C. Tubular cell–Escherichia coli interaction products modulate migration of monocytes through generation of transforming growth factor-β and macrophage–monocyte chemoattractant protein-1. J. Endourol. 16, 599–603 (2002).

    Article  PubMed  Google Scholar 

  121. Zhao, M. Electrical fields in wound healing — an overriding signal that directs cell migration. Semin. Cell Dev. Biol. 20, 674–682 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Zhao, M. et al. Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-γ and PTEN. Nature 442, 457–460 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Reid, B., Song, B., McCaig, C. D., & Zhao, M. Wound healing in rat cornea: the role of electric currents. FASEB J. 19, 379–386 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nature Rev. Mol. Cell Biol. 13, 283–296 (2012).

    Article  CAS  Google Scholar 

  125. Nehrt, A., Rodgers, R., Shapiro, S., Borgens, R. & Shi, R. The critical role of voltage-dependent calcium channel in axonal repair following mechanical trauma. Neuroscience 146, 1504–1512 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Dubé, J. et al. Restoration of the transepithelial potential within tissue-engineered human skin in vitro and during the wound healing process in vivo. Tissue Eng. Part A 16, 3055–3063 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Tapon, N. & Hall, A. Rho, Rac and Cdc42 GTPases regulate the organization of the actin cytoskeleton. Curr. Opin. Cell Biol. 9, 86–92 (1997).

    Article  CAS  PubMed  Google Scholar 

  128. Wennerberg, K. Rho-family GTPases: it's not only Rac and Rho (and I like it). J. Cell Sci. 117, 1301–1312 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Bass, M. D. et al. A syndecan-4 hair trigger initiates wound healing through caveolin- and RhoG-regulated integrin endocytosis. Dev. Cell 21, 681–693 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Rossman, K. L., Der, C. J. & Sondek, J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nature Rev. Mol. Cell Biol. 6, 167–180 (2005).

    Article  CAS  Google Scholar 

  131. Vaughan, E. M., Miller, A. L., Yu, H.-Y. E. & Bement, W. M. Control of local Rho GTPase crosstalk by Abr. Curr. Biol. 21, 270–277 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Caddy, J. et al. Epidermal wound repair is regulated by the planar cell polarity signaling pathway. Dev. Cell 19, 138–147 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Rodriguez Diaz, A. et al. Actomyosin purse strings: renewable resources that make morphogenesis robust and resilient. HFSP J. 2, 220–237 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Rizo, J. & Südhof, T. C. C2-domains, structure and function of a universal Ca2+-binding domain. J. Biol. Chem. 273, 15879–15882 (1998).

    Article  CAS  PubMed  Google Scholar 

  135. Samarin, S. N., Ivanov, A. I., Flatau, G., Parkos, C. A. & Nusrat, A. Rho/Rho-associated kinase-II signaling mediates disassembly of epithelial apical junctions. Mol. Biol. Cell 18, 3429–3439 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Guilluy, C. et al. The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins. Nature Cell Biol. 13, 722–727 (2011).

    Article  CAS  PubMed  Google Scholar 

  137. Mattila, J., Omelyanchuk, L., Kyttala, S., Turunen, H. & Nokkala, S. Role of Jun N-terminal kinase (JNK) signaling in the wound healing and regeneration of a Drosophila melanogaster wing imaginal disc. Int. J. Dev. Biol. 49, 391–399 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  139. Mace, K. A., Pearson, J. C. & McGinnis, W. An epidermal barrier wound repair pathway in Drosophila is mediated by grainy head. Science 308, 381–385 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Godell, C. M. et al. Calpain activity promotes the sealing of severed giant axons. Proc. Natl Acad. Sci. USA 94, 4751–4756 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Robinson, R. C. et al. Domain movement in gelsolin: a calcium-activated switch. Science 286, 1939–1942 (1999).

    Article  CAS  PubMed  Google Scholar 

  142. Yin, J. & Yu, F.-S. X. ERK1/2 mediate wounding- and G-protein-coupled receptor ligands-induced EGFR activation via regulating ADAM17 and HB-EGF shedding. Invest. Ophthalmol. Vis. Sci. 50, 132–139 (2008).

    Article  PubMed  Google Scholar 

  143. Harper, R. W. et al. Differential regulation of dual NADPH oxidases/peroxidases, Duox1 and Duox2, by Th1 and Th2 cytokines in respiratory tract epithelium. FEBS Lett. 579, 4911–4917 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Lambeth, J. D. NOX enzymes and the biology of reactive oxygen. Nature Rev. Immunol. 4, 181–189 (2004).

    Article  CAS  Google Scholar 

  145. Ha, E.-M. et al. Regulation of DUOX by the Gαq–phospholipase Cβ–Ca2+ pathway in Drosophila gut immunity. Dev. Cell 16, 386–397 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Wesley, U. V., Bove, P. F., Hristova, M., McCarthy, S. & van der Vliet, A. Airway epithelial cell migration and wound repair by ATP-mediated activation of dual oxidase 1. J. Biol. Chem. 282, 3213–3220 (2007).

    Article  CAS  PubMed  Google Scholar 

  147. Juarez, M. T., Patterson, R. A., Sandoval-Guillen, E. & McGinnis, W. Duox, flotillin-2, and Src42A are required to activate or delimit the spread of the transcriptional response to epidermal wounds in Drosophila. PLoS Genet. 7, e1002424 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Roy, S., Khanna, S., Rink, C., Biswas, S. & Sen, C. K. Characterization of the acute temporal changes in excisional murine cutaneous wound inflammation by screening of the wound-edge transcriptome. Physiol. Genom. 34, 162–184 (2008).

    Article  CAS  Google Scholar 

  149. Pearson, J. C., Juarez, M. T., Kim, M., Drivenes, Ø. & McGinnis, W. Multiple transcription factor codes activate epidermal wound-response genes in Drosophila. Proc. Natl Acad. Sci. USA 106, 2224–2229 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Lesch, C., Jo, J., Wu, Y., Fish, G. S. & Galko, M. J. A targeted UAS-RNAi screen in Drosophila larvae identifies wound closure genes regulating distinct cellular processes. Genetics 186, 943–957 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Wolpert, L. Positional information and patterning revisited. J. Theor. Biol. 269, 359–365 (2011).

    Article  PubMed  Google Scholar 

  152. Tucker, P. K., Evans, I. R. & Wood, W. Ena drives invasive macrophage migration in Drosophila embryos. Dis. Model. Mech. 4, 126–134 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Stramer, B. et al. Live imaging of wound inflammation in Drosophila embryos reveals key roles for small GTPases during in vivo cell migration. J. Cell Biol. 168, 567–573 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Klemke, M. et al. Oxidation of cofilin mediates T cell hyporesponsiveness under oxidative stress conditions. Immunity 29, 404–413 (2008).

    Article  CAS  PubMed  Google Scholar 

  155. Milzani, A. et al. The oxidation produced by hydrogen peroxide on Ca–ATP–G-actin. Protein Sci. 9, 1774–1782 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Aghajanian, A., Wittchen, E. S., Campbell, S. L. & Burridge, K. Direct activation of RhoA by reactive oxygen species requires a redox-sensitive motif. PLoS ONE 4, e8045 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Seminario-Vidal, L. et al. Thrombin promotes release of ATP from lung epithelial cells through coordinated activation of Rho- and Ca2+-dependent signaling pathways. J. Biol. Chem. 284, 20638–20648 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Huttenlocher, A. & Poznansky, M. C. Reverse leukocyte migration can be attractive or repulsive. Trends Cell Biol. 18, 298–306 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Hochreiter-Hufford, A. & Ravichandran, K. S. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb. Perspect. Biol. 5, a008748 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Mammano, F. ATP-dependent intercellular Ca2+ signaling in the developing cochlea: facts, fantasies and perspectives. Semin. Cell Dev. Biol. 24, 31–39 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Buvinic, S. et al. ATP released by electrical stimuli elicits calcium transients and gene expression in skeletal muscle. J. Biol. Chem. 284, 34490–34505 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Arcuino, G. et al. Intercellular calcium signaling mediated by point-source burst release of ATP. Proc. Natl Acad. Sci. USA 99, 9840–9845 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Gonzalez, F. A., Rozengurt, E. & Heppel, L. A. Extracellular ATP induces the release of calcium from intracellular stores without the activation of protein kinase C in Swiss 3T6 mouse fibroblasts. Proc. Natl Acad. Sci. USA 86, 4530–4534 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Sivaramakrishnan, V., Bidula, S., Campwala, H., Katikaneni, D. & Fountain, S. J. Constitutive lysosome exocytosis releases ATP and engages P2Y receptors in human monocytes. J. Cell Sci. 125, 4567–4575 (2012).

    Article  CAS  PubMed  Google Scholar 

  165. Zhang, Z. et al. Regulated ATP release from astrocytes through lysosome exocytosis. Nature Cell Biol. 9, 945–953 (2007).

    Article  CAS  PubMed  Google Scholar 

  166. Shabir, S. & Southgate, J. Calcium signalling in wound-responsive normal human urothelial cell monolayers. Cell Calcium 44, 453–464 (2008).

    Article  CAS  PubMed  Google Scholar 

  167. Block, G. J., DiMattia, G. D. & Prockop, D. J. Stanniocalcin-1 regulates extracellular ATP-induced calcium waves in human epithelial cancer cells by stimulating ATP release from bystander cells. PLoS ONE 5, e10237 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Yeung, B. H. Y. & Wong, C. K. C. Stanniocalcin-1 regulates re-epithelialization in human keratinocytes. PLoS ONE 6, e27094 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Geiger, J. A., Carvalho, L., Campos, I., Santos, A. C. & Jacinto, A. Hole-in-one mutant phenotypes link EGFR/ERK signaling to epithelial tissue repair in Drosophila. PLoS ONE 6, e28349 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Kim, M. & McGinnis, W. Phosphorylation of Grainy head by ERK is essential for wound-dependent regeneration but not for development of an epidermal barrier. Proc. Natl Acad. Sci. USA 108, 650–655 (2011).

    Article  CAS  PubMed  Google Scholar 

  171. Ciapponi, L., Jackson, D. B., Mlodzik, M. & Bohmann, D. Drosophila Fos mediates ERK and JNK signals via distinct phosphorylation sites. Genes Dev. 15, 1540–1553 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Kanellis, J. et al. Stanniocalcin-1, an inhibitor of macrophage chemotaxis and chemokinesis. Am. J. Physiol. Renal Physiol. 286, F356–F362 (2004).

    Article  CAS  PubMed  Google Scholar 

  173. Chakraborty, A. et al. Stanniocalcin-1 regulates endothelial gene expression and modulates transendothelial migration of leukocytes. Am. J. Physiol. Renal Physiol. 292, F895–F904 (2006).

    Article  CAS  PubMed  Google Scholar 

  174. Hoffman, B. D., Grashoff, C. & Schwartz, M. A. Dynamic molecular processes mediate cellular mechanotransduction. Nature 475, 316–323 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Galkin, V. E., Orlova, A. & Egelman, E. H. Actin filaments as tension sensors. Curr. Biol. 22, R96–R101 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Árnadóttir, J. & Chalfie, M. Eukaryotic mechanosensitive channels. Annu. Rev. Biophys. 39, 111–137 (2010).

    Article  CAS  PubMed  Google Scholar 

  177. Stabley, D. R., Jurchenko, C., Marshall, S. S. & Salaita, K. S. Visualizing mechanical tension across membrane receptors with a fluorescent sensor. Nature Methods 9, 64–67 (2011).

    Article  CAS  PubMed  Google Scholar 

  178. Harrison, D. G. et al. Endothelial mechanotransduction, nitric oxide and vascular inflammation. J. Intern. Med. 259, 351–363 (2006).

    Article  CAS  PubMed  Google Scholar 

  179. Wong, V. W., Longaker, M. T. & Gurtner, G. C. Soft tissue mechanotransduction in wound healing and fibrosis. Semin. Cell Dev. Biol. 23, 981–986 (2012).

    Article  CAS  PubMed  Google Scholar 

  180. Leckband, D. E., le Duc, Q., Wang, N. & de Rooij, J. Mechanotransduction at cadherin-mediated adhesions. Curr. Opin. Cell Biol. 23, 523–530 (2011).

    Article  CAS  PubMed  Google Scholar 

  181. Kolega, J. Effects of mechanical tension on protrusive activity and microfilament and intermediate filament organization in an epidermal epithelium moving in culture. J. Cell Biol. 102, 1400–1411 (1986).

    Article  CAS  PubMed  Google Scholar 

  182. Glogauer, M. et al. Calcium ions and tyrosine phosphorylation interact coordinately with actin to regulate cytoprotective responses to stretching. J. Cell Sci. 110, 11–21 (1997).

    CAS  PubMed  Google Scholar 

  183. Hayakawa, K., Tatsumi, H. & Sokabe, M. Actin stress fibers transmit and focus force to activate mechanosensitive channels. J. Cell Sci. 121, 496–503 (2008).

    Article  CAS  PubMed  Google Scholar 

  184. Parsons, J. T., Horwitz, A. R. & Schwartz, M. A. Cell adhesion: integrating cytoskeletal dynamics and cellular tension. Nature Rev. Mol. Cell Biol. 11, 633–643 (2010).

    Article  CAS  Google Scholar 

  185. Ko, K. S., Arora, P. D. & McCulloch, C. A. Cadherins mediate intercellular mechanical signaling in fibroblasts by activation of stretch-sensitive calcium-permeable channels. J. Biol. Chem. 276, 35967–35977 (2001).

    Article  CAS  PubMed  Google Scholar 

  186. McNeil, P. L., Muthukrishnan, L., Warder, E. & D'Amore, P. A. Growth factors are released by mechanically wounded endothelial cells. J. Cell Biol. 109, 811–822 (1989).

    Article  CAS  PubMed  Google Scholar 

  187. Wang, Sen, Lee, J., Ro, J. Y. & Chung, M.-K. Warmth suppresses and desensitizes damage-sensing ion channel TRPA1. Mol. Pain 8, 22 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Liman, E. R. Thermal gating of TRP ion channels: food for thought? Sci. STKE 2006, pe12 (2006).

    PubMed  Google Scholar 

  189. Raya, A. et al. Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination. Nature 427, 121–128 (2004).

    Article  CAS  PubMed  Google Scholar 

  190. Odell, G. M., Oster, G., Alberch, P. & Burnside, B. The mechanical basis of morphogenesis. I. Epithelial folding and invagination. Dev. Biol. 85, 446–462 (1981).

    Article  CAS  PubMed  Google Scholar 

  191. Richardson, R. et al. Adult zebrafish as a model system for cutaneous wound healing research. J. Invest. Dermatol. 16 Jan 2013 (doi:10.1038/jid.2013.16).

  192. Yoo, S. K., Starnes, T. W., Deng, Q. & Huttenlocher, A. Lyn is a redox sensor that mediates leukocyte wound attraction in vivo. Nature 480, 109–112 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

J.V.C. and A.J. are funded by Fundaçâo para a Ciência e a Tecnologia, Instituto Gulbenkian de Ciência and by a European Research Council Starting Grant (2007-StG-208631).

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    João V. Cordeiro & António Jacinto

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Glossary

Dorsal closure

A characteristic morphogenetic process in Drosophila melanogaster embryogenesis. During dorsal closure, opposing sheets of epithelial cells move across to seal a large gap in the epithelium, thus providing a good model for wound healing studies.

Platelet

A small anucleated cell that circulates in the blood and is essential for blood coagulation by aggregating and forming blood clots.

Inflammation

A biological process aimed at restoring normal cellular function following infection or cellular damage. It engages the vascular and immune systems and involves various cell types such as platelets, neutrophils and macrophages.

Transcription-independent diffusible damage signals

Molecules that are formed or recruited as a result of damage. They can diffuse through tissues to promote immediate cellular responses in a manner that is independent of gene transcription.

Wound response genes

Genes that are up- or downregulated in cells involved in wound healing. They are important for the regulation of the wound healing process and include, for example, genes encoding grainy head, actin regulators and receptor Tyr kinases.

Wound leading edge

The region that contains wound margin cells, which lead the epithelial repair response.

Actomyosin cables

Subcellular structures that consist of accumulated F-actin and myosin II. These structures form at the base of wound margin cells and connect through cadherin-mediated adhesion to neighbouring cells. The anchoring on neighbouring cells coupled with sliding of myosin II motors along actin filaments provides the necessary contractile force to seal wounds by a characteristic purse-string mechanism.

RHO GTPases

Small signalling G proteins found in all eukaryotes. They regulate cell biological processes such as cell division, apoptosis, cell adhesion and cell migration, and they have essential roles in the regulation of the actin cytoskeleton and actomyosin contractility.

Lamellipodia

Wide and flat cellular protrusions of motile cells and wound leading edge cells that are driven by RHO GTPase-regulated actin polymerization.

Filopodia

Narrow and long cellular protrusions of motile cells and wound leading edge cells that are driven by RHO GTPase-regulated actin bundling.

Macrophages

Immune defence cells resulting from monocyte differentiation in tissues that have a role in both innate and adaptive immunity by searching for and phagocytosing cell debris and pathogens. Macrophages also contribute to inflammation by secreting factors that attract and stimulate other immune cells.

Neutrophils

White blood cells that are normally found in the blood stream. They can migrate quickly towards sites of infection or inflammation in response to a chemical signal. Neutrophils have the capacity to phagocytose pathogens, release antimicrobial factors and form fibres of chromatin and proteases that trap and kill microorganisms.

GCaMP calcium indicators

Genetically encoded circularly permuted fluorescent proteins. They enable the detection and measurement of rapid changes in cytosolic Ca2+ levels by using the Ca2+-dependent interaction between calmodulin and a synthetic peptide (M13), which is based on the calmodulin-binding domain of the skeletal muscle myosin light chain kinase.

Metalloproteinases

Enzymes that catalyse the hydrolysis of peptide bonds within proteins in the presence of metals such as zinc or cobalt.

HyPer

A genetically encoded circularly permuted fluorescent protein that enables the specific detection and measurement of changes in intracellular H2O2 levels by making use of the peroxide-sensing properties of the prokaryotic protein OxyR (H2O2 -inducible genes activator).

Microglia

Resident macrophages of the central nervous system that have essential immune defence scavenging properties for pathogens, extracellular deposits of amyloid and damaged or dying neurons.

Corpse signals

Molecules released by apoptotic cells that alert phagocytic cells of the immune system. These signals include fractalkine, lysophosphatidylcholine, sphingosine 1-phosphate, ATP and UTP.

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Cordeiro, J., Jacinto, A. The role of transcription-independent damage signals in the initiation of epithelial wound healing. Nat Rev Mol Cell Biol 14, 249–262 (2013). https://doi.org/10.1038/nrm3541

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