Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cellular and molecular mechanisms of skin wound healing

Nature Reviews Molecular Cell Biology (2024)Cite this article

Subjects

Abstract

Wound healing is a complex process that involves the coordinated actions of many different tissues and cell lineages. It requires tight orchestration of cell migration, proliferation, matrix deposition and remodelling, alongside inflammation and angiogenesis. Whereas small skin wounds heal in days, larger injuries resulting from trauma, acute illness or major surgery can take several weeks to heal, generally leaving behind a fibrotic scar that can impact tissue function. Development of therapeutics to prevent scarring and successfully repair chronic wounds requires a fuller knowledge of the cellular and molecular mechanisms driving wound healing. In this Review, we discuss the current understanding of the different phases of wound healing, from clot formation through re-epithelialization, angiogenesis and subsequent scar deposition. We highlight the contribution of different cell types to skin repair, with emphasis on how both innate and adaptive immune cells in the wound inflammatory response influence classically studied wound cell lineages, including keratinocytes, fibroblasts and endothelial cells, but also some of the less-studied cell lineages such as adipocytes, melanocytes and cutaneous nerves. Finally, we discuss newer approaches and research directions that have the potential to further our understanding of the mechanisms underpinning tissue repair.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Phases of wound healing.
Fig. 2: Early signals travelling through the epithelium.
Fig. 3: The wound inflammatory response and the roles of neutrophils and macrophages in wound healing.
Fig. 4: Role of fibroblasts in regulating ECM remodelling at the wound site.
Fig. 5: Roles of other cell types in wound healing.

Similar content being viewed by others

References

  1. de Bont, C. M., Boelens, W. C. & Pruijn, G. J. M. NETosis, complement, and coagulation: a triangular relationship. Cell. Mol. Immunol. 16, 19–27 (2019).

    Article  PubMed  Google Scholar 

  2. Berntorp, E. et al. Haemophilia. Nat. Rev. Dis. Prim. 7, 45 (2021).

    Article  PubMed  Google Scholar 

  3. Peyvandi, F., Bolton-Maggs, P. H., Batorova, A. & De Moerloose, P. Rare bleeding disorders. Haemophilia 18, 148–153 (2012).

    Article  PubMed  Google Scholar 

  4. Golebiewska, E. M. & Poole, A. W. Platelet secretion: from haemostasis to wound healing and beyond. Blood Rev. 29, 153–162 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Szpaderska, A. M., Egozi, E. I., Gamelli, R. L. & DiPietro, L. A. The effect of thrombocytopenia on dermal wound healing. J. Invest. Dermatol. 120, 1130–1137 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Gaertner, F. & Massberg, S. Blood coagulation in immunothrombosis — at the frontline of intravascular immunity. Semin. Immunol. 28, 561–569 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Burzynski, L. C. et al. The coagulation and immune systems are directly linked through the activation of interleukin-1α by thrombin. Immunity 50, 1033–1042.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Garlick, J. A. & Taichman, L. B. Fate of human keratinocytes during reepithelialization in an organotypic culture model. Lab. Invest. 70, 916–924 (1994).

    CAS  PubMed  Google Scholar 

  9. Matoltsy, A. G. & Viziam, C. B. Further observations on epithelialization of small wounds: an autoradiographic study of incorporation and distribution of 3H-thymidine in the epithelium covering skin wounds. J. Invest. Dermatol. 55, 20–25 (1970).

    Article  CAS  PubMed  Google Scholar 

  10. Park, S. et al. Tissue-scale coordination of cellular behaviour promotes epidermal wound repair in live mice. Nat. Cell Biol. 19, 155–163 (2017). Despite it being extremely difficult, this study shows live imaging of wound epidermal cells as they migrate during healing of mammalian skin. Additionally, the migratory tracks are clear and show how there is a zone of cell division back from the migratory front. This study even hints at orientation of wound-induced cell divisions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Aragona, M. et al. Defining stem cell dynamics and migration during wound healing in mouse skin epidermis. Nat. Commun. 8, 14684 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Turley, J., Chenchiah, I. V., Martin, P., Liverpool, T. B. & Weavers, H. Deep learning for rapid analysis of cell divisions in vivo during epithelial morphogenesis and repair. eLife https://doi.org/10.7554/elife.87949.1 (2023).

  13. Molinie, N. & Gautreau, A. Directional collective migration in wound healing assays. Methods Mol. Biol. 1749, 11–19 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Gudipaty, S. A. et al. Mechanical stretch triggers rapid epithelial cell division through Piezo1. Nature 543, 118–121 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Werner, S. et al. Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc. Natl Acad. Sci. USA 89, 6896–6900 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Werner, S. et al. The function of KGF in morphogenesis of epithelium and reepithelialization of wounds. Science 266, 819–822 (1994). Before this study, several growth factors had been applied to wounds to enhance repair, but this study and its sister paper (Werner et al.15) showed that KGF (also known as FGF7) is upregulated by wound dermal cells and, if its receptor is inactivated in keratinocytes, then wound healing is blocked.

    Article  CAS  PubMed  Google Scholar 

  17. Meyer, M. et al. FGF receptors 1 and 2 are key regulators of keratinocyte migration in vitro and in wounded skin. J. Cell Sci. 125, 5690–5701 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gallini, S. et al. Injury prevents Ras mutant cell expansion in mosaic skin. Nature 619, 167–175 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Barrientos, S., Stojadinovic, O., Golinko, M. S., Brem, H. & Tomic-Canic, M. Growth factors and cytokines in wound healing. Wound Repair Regen. 16, 585–601 (2008).

    Article  PubMed  Google Scholar 

  21. Chmielowiec, J. et al. c-Met is essential for wound healing in the skin. J. Cell Biol. 177, 151–162 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Grose, R., Harris, B. S., Cooper, L., Topilko, P. & Martin, P. Immediate early genes krox-24 and krox-20 are rapidly up-regulated after wounding in the embryonic and adult mouse. Dev. Dyn. 223, 371–378 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Martin, P. & Nobes, C. D. An early molecular component of the wound healing response in rat embryos — induction of c-fos protein in cells at the epidermal wound margin. Mech. Dev. 38, 209–215 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. 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  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yu, H. et al. Landscape of the epigenetic regulation in wound healing. Front. Physiol. 13, 949498 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Shaw, T. & Martin, P. Epigenetic reprogramming during wound healing: loss of polycomb-mediated silencing may enable upregulation of repair genes. EMBO Rep. 10, 881–886 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Naik, S. et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550, 475–480 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Naik, S. & Fuchs, E. Inflammatory memory and tissue adaptation in sickness and in health. Nature 607, 249–255 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Levra Levron, C. et al. Tissue memory relies on stem cell priming in distal undamaged areas. Nat. Cell Biol. 25, 740–753 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gonzales, K. A. U. et al. Stem cells expand potency and alter tissue fitness by accumulating diverse epigenetic memories. Science 374, eabh2444 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wood, W. et al. Wound healing recapitulates morphogenesis in Drosophila embryos. Nat. Cell Biol. 4, 907–912 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Haensel, D. et al. Defining epidermal basal cell states during skin homeostasis and wound healing using single-cell transcriptomics. Cell Rep. 30, 3932–3947.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schäfer, M. & Werner, S. Cancer as an overhealing wound: an old hypothesis revisited. Nat. Rev. Mol. Cell Biol. 9, 628–638 (2008).

    Article  PubMed  Google Scholar 

  34. Grose, R. et al. A crucial role of β1 integrins for keratinocyte migration in vitro and during cutaneous wound repair. Development 129, 2303–2315 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Jacobsen, J. N., Steffensen, B., Häkkinen, L., Krogfelt, K. A. & Larjava, H. S. Skin wound healing in diabetic β6 integrin-deficient mice. APMIS 118, 753–764 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McAndrews, K. M. et al. Dermal αSMA+ myofibroblasts orchestrate skin wound repair via β1 integrin and independent of type I collagen production. EMBO J. 41, e109470 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Singh, P. et al. Loss of integrin α9β1 results in defects in proliferation, causing poor re-epithelialization during cutaneous wound healing. J. Invest. Dermatol. 129, 217–228 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Liu, S. et al. Expression of integrin β1 by fibroblasts is required for tissue repair in vivo. J. Cell Sci. 123, 3674–3682 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Reynolds, L. E. et al. Accelerated re-epithelialization in β3-integrin-deficient mice is associated with enhanced TGF-β1 signaling. Nat. Med. 11, 167–174 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Hertle, M. D., Kubler, M. D., Leigh, I. M. & Watt, F. M. Aberrant integrin expression during epidermal wound healing and in psoriatic epidermis. J. Clin. Invest. 89, 1892–1901 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zweers, M. C. et al. Integrin α2β1 is required for regulation of murine wound angiogenesis but is dispensable for reepithelialization. J. Invest. Dermatol. 127, 467–478 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Rohani, M. G. & Parks, W. C. Matrix remodeling by MMPs during wound repair. Matrix Biol. 44-46, 113–121 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Tetley, R. J. et al. Tissue fluidity promotes epithelial wound healing. Nat. Phys. 15, 1195–1203 (2019). This paper is a mathematical biology study in Drosophila that shows how critical cell intercalations back from the leading edge make the epithelium more 'fluid' and enable wound re-epithelialization.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Razzell, W., Wood, W. & Martin, P. Recapitulation of morphogenetic cell shape changes enables wound re-epithelialisation. Development 141, 1814–1820 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Vu, R., Dragan, M., Sun, P., Werner, S. & Dai, X. Epithelial-mesenchymal plasticity and endothelial-mesenchymal transition in cutaneous wound healing. Cold Spring Harb. Perspect. Biol. 15, a041237 (2023).

    Article  CAS  PubMed  Google Scholar 

  46. Nunan, R. et al. Ephrin-Bs drive junctional downregulation and actin stress fiber disassembly to enable wound re-epithelialization. Cell Rep. 13, 1380–1395 (2015). The study reveals how Eph–ephrin signalling enables partial epithelial-to-mesenchymal transition in the advancing wound epithelium by downregulating adherens and tight junctions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Weavers, H., Wood, W. & Martin, P. Injury activates a dynamic cytoprotective network to confer stress resilience and drive repair. Curr. Biol. 29, 3851–3862.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Telorack, M. et al. A glutathione-Nrf2-thioredoxin cross-talk ensures keratinocyte survival and efficient wound repair. PLoS Genet. 12, e1005800 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Stramer, B. et al. Gene induction following wounding of wild-type versus macrophage-deficient Drosophila embryos. EMBO Rep. 9, 465–471 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rompolas, P., Mesa, K. R. & Greco, V. Spatial organization within a niche as a determinant of stem-cell fate. Nature 502, 513–518 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hoeck, J. D. et al. Stem cell plasticity enables hair regeneration following Lgr5+ cell loss. Nat. Cell Biol. 19, 666–676 (2017).

    Article  CAS  PubMed  Google Scholar 

  52. Braun, K. M. et al. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 130, 5241–5255 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nat. Biotechnol. 22, 411–417 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Taylor, G., Lehrer, M. S., Jensen, P. J., Sun, T.-T. & Lavker, R. M. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102, 451–461 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Claudinot, S., Nicolas, M., Oshima, H., Rochat, A. & Barrandon, Y. Long-term renewal of hair follicles from clonogenic multipotent stem cells. Proc. Natl Acad. Sci. USA 102, 14677–14682 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Oshima, H., Rochat, A., Kedzia, C., Kobayashi, K. & Barrandon, Y. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell 104, 233–245 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Ito, M. et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447, 316–320 (2007). The remarkable findings by Ito et al. were the first to demonstrate that new hair follicles could form de novo in a wound bed and that induction of these hair follicles is dependent on Wnt signalling.

    Article  CAS  PubMed  Google Scholar 

  60. Myung, P. S., Takeo, M., Ito, M. & Atit, R. P. Epithelial Wnt ligand secretion is required for adult hair follicle growth and regeneration. J. Invest. Dermatol. 133, 31–41 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Lee, P. et al. Stimulation of hair follicle stem cell proliferation through an IL-1 dependent activation of γδT-cells. eLife 6, e28875 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Liu, Z. et al. Glucocorticoid signaling and regulatory T cells cooperate to maintain the hair-follicle stem-cell niche. Nat. Immunol. 23, 1086–1097 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gay, D. et al. Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding. Nat. Med. 19, 916–923 (2013). This study demonstrates that dermal γδ T cells promote hair follicle regeneration in wounds by production of FGF9, which activates Wnt signalling in fibroblasts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Panteleyev, A. A., Rosenbach, T., Paus, R. & Christiano, A. M. The bulge is the source of cellular renewal in the sebaceous gland of mouse skin. Arch. Dermatol. Res. 292, 573–576 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Frances, D. & Niemann, C. Stem cell dynamics in sebaceous gland morphogenesis in mouse skin. Dev. Biol. 363, 138–146 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Weng, T. et al. Regeneration of skin appendages and nerves: current status and further challenges. J. Transl. Med. 18, 53 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Lu, C. P. et al. Identification of stem cell populations in sweat glands and ducts reveals roles in homeostasis and wound repair. Cell 150, 136–150 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chen, L., Zhang, M., Li, H., Tang, S. & Fu, X. Distribution of BrdU label-retaining cells in eccrine sweat glands and comparison of the percentage of BrdU-positive cells in eccrine sweat glands and in epidermis in rats. Arch. Dermatol. Res. 306, 157–162 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020).

    Article  CAS  PubMed  Google Scholar 

  71. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Razzell, W., Evans, I. R., Martin, P. & Wood, W. Calcium flashes orchestrate the wound inflammatory response through DUOX activation and hydrogen peroxide release. Curr. Biol. 23, 424–429 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xu, S. & Andrew, C. A Gαq-Ca2+ signaling pathway promotes actin-mediated epidermal wound closure in C. elegans. Curr. Biol. 21, 1960–1967 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Boucher, I., Rich, C., Lee, A., Marcincin, M. & Trinkaus-Randall, V. The P2Y2 receptor mediates the epithelial injury response and cell migration. Am. J. Physiol. Cell Physiol. 299, C411–C421 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. de Oliveira, S. et al. ATP modulates acute inflammation in vivo through dual oxidase 1-derived H2O2 production and NF-κB activation. J. Immunol. 192, 5710–5719 (2014).

    Article  PubMed  Google Scholar 

  78. Antunes, M., Pereira, T., Cordeiro, J. V., Almeida, L. & Jacinto, A. Coordinated waves of actomyosin flow and apical cell constriction immediately after wounding. J. Cell Biol. 202, 365–379 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 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).

    Article  CAS  PubMed  Google Scholar 

  80. Katikaneni, A. et al. Lipid peroxidation regulates long-range wound detection through 5-lipoxygenase in zebrafish. Nat. Cell Biol. 22, 1049–1055 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678–689 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. De Oliveira, S., Rosowski, E. E. & Huttenlocher, A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat. Rev. Immunol. 16, 378–391 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Chu, J. Y., McCormick, B. & Vermeren, S. Small GTPase-dependent regulation of leukocyte–endothelial interactions in inflammation. Biochem. Soc. Trans. 46, 649–658 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Lämmermann, T. et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498, 371–375 (2013).

    Article  PubMed  Google Scholar 

  85. Isles, H. M. et al. Pioneer neutrophils release chromatin within in vivo swarms. eLife 10, e68755 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lewis, H. D. et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat. Chem. Biol. 11, 189–191 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Chen, K. W. et al. Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps. Sci. Immunol. 3, eaar6676 (2018).

    Article  PubMed  Google Scholar 

  88. Sollberger, G. et al. Gasdermin D plays a vital role in the generation of neutrophil extracellular traps. Sci. Immunol. 3, eaar6689 (2018).

    Article  PubMed  Google Scholar 

  89. Papayannopoulos, V., Metzler, K. D., Hakkim, A. & Zychlinsky, A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J. Cell Biol. 191, 677–691 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Grice, E. A. & Segre, J. A. In Current Topics in Innate Immunity II (eds Lambris, J. & Hajishengallis, G.) 55–68 (Springer New York, 2012).

  91. Maitz, J., Merlino, J., Rizzo, S., McKew, G. & Maitz, P. Burn wound infections microbiome and novel approaches using therapeutic microorganisms in burn wound infection control. Adv. Drug Deliv. Rev. 196, 114769 (2023).

    Article  CAS  PubMed  Google Scholar 

  92. Fischer, A. et al. Neutrophils direct preexisting matrix to initiate repair in damaged tissues. Nat. Immunol. 23, 518–531 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Medeiros, A. I., Serezani, C. H., Lee, S. P. & Peters-Golden, M. Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling. J. Exp. Med. 206, 61–68 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bellingan, G. J., Caldwell, H., Howie, S. E., Dransfield, I. & Haslett, C. In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes. J. Immunol. 157, 2577–2585 (1996).

    Article  CAS  PubMed  Google Scholar 

  95. Mathias, J. R. et al. Resolution of inflammation by retrograde chemotaxis of neutrophils in transgenic zebrafish. J. Leukoc. Biol. 80, 1281–1288 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Elks, P. M. et al. Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. Blood 118, 712–722 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Woodfin, A. et al. The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nat. Immunol. 12, 761–769 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wang, J. et al. Visualizing the function and fate of neutrophils in sterile injury and repair. Science 358, 111–116 (2017).

    Article  CAS  PubMed  Google Scholar 

  99. Phillipson, M. & Kubes, P. The healing power of neutrophils. Trends Immunol. 40, 635–647 (2019).

    Article  CAS  PubMed  Google Scholar 

  100. Wong, S. L. et al. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat. Med. 21, 815–819 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Fadini, G. P. et al. NETosis delays diabetic wound healing in mice and humans. Diabetes 65, 1061–1071 (2016).

    Article  CAS  PubMed  Google Scholar 

  102. Geissmann, F., Jung, S. & Littman, D. R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Yamasaki, S. et al. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat. Immunol. 9, 1179–1188 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Auffray, C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. DiPietro, L. A., Polverini, P. J., Rahbe, S. M. & Kovacs, E. J. Modulation of JE/MCP-1 expression in dermal wound repair. Am. J. Pathol. 146, 868–875 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Sheppe, A. E. F. & Edelmann, M. J. Roles of eicosanoids in regulating inflammation and neutrophil migration as an innate host response to bacterial infections. Infect. Immun. 89, e0009521 (2021).

    Article  PubMed  Google Scholar 

  107. Salina, A. C. G. et al. Leukotriene B4 licenses inflammasome activation to enhance skin host defense. Proc. Natl Acad. Sci. USA 117, 30619–30627 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Murray, P. J. Macrophage polarization. Annu. Rev. Physiol. 79, 541–566 (2017).

    Article  CAS  PubMed  Google Scholar 

  109. Belge, K. U. et al. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J. Immunol. 168, 3536–3542 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Stein, M., Keshav, S., Harris, N. & Gordon, S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J. Exp. Med. 176, 287–292 (1992).

    Article  CAS  PubMed  Google Scholar 

  111. Van Dyken, S. J. & Locksley, R. M. Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu. Rev. Immunol. 31, 317–343 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Crowther, M., Brown, N. J., Bishop, E. T. & Lewis, C. E. Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors. J. Leukoc. Biol. 70, 478–490 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Willenborg, S., Injarabian, L. & Eming, S. A. Role of macrophages in wound healing. Cold Spring Harb. Perspect. Biol. 14, a041216 (2022).

    Article  CAS  PubMed  Google Scholar 

  114. Eming, S. A., Murray, P. J. & Pearce, E. J. Metabolic orchestration of the wound healing response. Cell Metab. 33, 1726–1743 (2021).

    Article  CAS  PubMed  Google Scholar 

  115. Willenborg, S. et al. Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab. 33, 2398–2414.e9 (2021).

    Article  CAS  PubMed  Google Scholar 

  116. Ariel, A. & Serhan, C. N. New lives given by cell death: macrophage differentiation following their encounter with apoptotic leukocytes during the resolution of inflammation. Front. Immunol. 3, 4 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Horckmans, M. et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur. Heart J. 38, 187–197 (2017).

    CAS  PubMed  Google Scholar 

  118. Levy, B. D., Clish, C. B., Schmidt, B., Gronert, K. & Serhan, C. N. Lipid mediator class switching during acute inflammation: signals in resolution. Nat. Immunol. 2, 612–619 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Serhan, C. N. & Savill, J. Resolution of inflammation: the beginning programs the end. Nat. Immunol. 6, 1191–1197 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Freire-De-Lima, C. G. et al. Apoptotic cells, through transforming growth factor-β, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and no synthesis in murine macrophages. J. Biol. Chem. 281, 38376–38384 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Maddox, J. F. et al. Lipoxin A4 stable analogs are potent mimetics that stimulate human monocytes and THP-1 cells via a G-protein-linked lipoxin A4 receptor. J. Biol. Chem. 272, 6972–6978 (1997).

    Article  CAS  PubMed  Google Scholar 

  122. Soehnlein, O. & Lindbom, L. Phagocyte partnership during the onset and resolution of inflammation. Nat. Rev. Immunol. 10, 427–439 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Lucas, T. et al. Differential roles of macrophages in diverse phases of skin repair. J. Immunol. 184, 3964–3977 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Correa-Gallegos, D. et al. Patch repair of deep wounds by mobilized fascia. Nature 576, 287–292 (2019).

    Article  CAS  PubMed  Google Scholar 

  125. Driskell, R. R. et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277–281 (2013). This is the first of a series of papers from several labs that highlight how different spatial populations (even lineages) of fibroblasts in the skin have various phenotypes and contribute to wound healing in different ways that may help to explain how adult wounds scar and generally fail to regenerate appendages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Rinkevich, Y. et al. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science 348, aaa2151 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Jiang, D. et al. Two succeeding fibroblastic lineages drive dermal development and the transition from regeneration to scarring. Nat. Cell Biol. 20, 422–431 (2018).

    Article  CAS  PubMed  Google Scholar 

  128. Mascharak, S. et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science 372, eaba2374 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hopkinson-Woolley, J., Hughes, D., Gordon, S. & Martin, P. Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse. J. Cell Sci. 107, 1159–1167 (1994).

    Article  PubMed  Google Scholar 

  130. 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 

  131. Knipper, J. A. et al. Interleukin-4 receptor α signaling in myeloid cells controls collagen fibril assembly in skin repair. Immunity 43, 803–816 (2015). This study shows how IL-4Rα-activated macrophages induce expression of lysyl hydroxylase in wound effector fibroblasts, which leads to formation of more permanent cross-links between collagen fibrils and thus to more persistent scarring.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Mori, R., Shaw, T. J. & Martin, P. Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J. Exp. Med. 205, 43–51 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Piersma, B., Bank, R. A. & Boersema, M. Signaling in fibrosis: TGF-β, WNT, and YAP/TAZ converge. Front. Med. 2, 59 (2015).

    Article  Google Scholar 

  134. Gomes, R. N., Manuel, F. & Nascimento, D. S. The bright side of fibroblasts: molecular signature and regenerative cues in major organs. NPJ Regen. Med. 6, 43 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Jiang, D. et al. Injury triggers fascia fibroblast collective cell migration to drive scar formation through N-cadherin. Nat. Commun. 11, 5653 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Usansky, I. et al. A developmental basis for the anatomical diversity of dermis in homeostasis and wound repair. J. Pathol. 253, 315–325 (2021).

    Article  PubMed  Google Scholar 

  137. Ogawa, R., Mitsuhashi, K., Hyakusoku, H. & Miyashita, T. Postoperative electron-beam irradiation therapy for keloids and hypertrophic scars: retrospective study of 147 cases followed for more than 18 months. Plast. Reconstr. Surg. 111, 547–553 (2003).

    PubMed  Google Scholar 

  138. Sciubba, J. J., Waterhouse, J. P. & Meyer, J. A fine structural comparison of the healing of incisional wounds of mucosa and skin. J. Oral Pathol. 7, 214–227 (1978).

    Article  CAS  PubMed  Google Scholar 

  139. Szpaderska, A. M., Zuckerman, J. D. & DiPietro, L. A. Differential injury responses in oral mucosal and cutaneous wounds. J. Dent. Res. 82, 621–626 (2003).

    Article  CAS  PubMed  Google Scholar 

  140. Turabelidze, A. et al. Intrinsic differences between oral and skin keratinocytes. PLoS One 9, e101480 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Ogawa, R. Keloid and hypertrophic scarring may result from a mechanoreceptor or mechanosensitive nociceptor disorder. Med. Hypotheses 71, 493–500 (2008).

    Article  PubMed  Google Scholar 

  142. Wong, V. W. et al. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat. Med. 18, 148–152 (2011). This study was the first definitive demonstration that mechanical forces impact skin wound scarring and that this is mediated by FAK signalling, which in turn triggers increased inflammation.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Chen, K. et al. Disrupting biological sensors of force promotes tissue regeneration in large organisms. Nat. Commun. 12, 5256 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Chen, K. et al. Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting. Sci. Transl. Med. 14, eabj9152 (2022).

    Article  CAS  PubMed  Google Scholar 

  145. Holt, J. R. et al. Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing. eLife 10, e65415 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Sedov, E. et al. THY1-mediated mechanisms converge to drive YAP activation in skin homeostasis and repair. Nat. Cell Biol. 24, 1049–1063 (2022).

    Article  CAS  PubMed  Google Scholar 

  147. Maden, M. Optimal skin regeneration after full thickness thermal burn injury in the spiny mouse, Acomys cahirinus. Burns 44, 1509–1520 (2018).

    Article  PubMed  Google Scholar 

  148. Seifert, A. W. et al. Skin shedding and tissue regeneration in African spiny mice (Acomys). Nature 489, 561–565 (2012). This was the first report describing an African mouse species with remarkable skin (and other tissue) regenerative capacity, which has led to comparative studies to unravel the mechanisms underpinning its exceptional healing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Brant, J. O., Yoon, J. H., Polvadore, T., Barbazuk, W. B. & Maden, M. Cellular events during scar-free skin regeneration in the spiny mouse, Acomys. Wound Repair Regen. 24, 75–88 (2016).

    Article  PubMed  Google Scholar 

  150. Brewer, C. M. et al. Adaptations in Hippo-Yap signaling and myofibroblast fate underlie scar-free ear appendage wound healing in spiny mice. Dev. Cell 56, 2722–2740.e6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Nissen, N. N. et al. Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am. J. Pathol. 152, 1445–1452 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Urao, N. et al. MicroCT angiography detects vascular formation and regression in skin wound healing. Microvasc. Res. 106, 57–66 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Rebling, J., Ben‐Yehuda Greenwald, M., Wietecha, M., Werner, S. & Razansky, D. Long‐term imaging of wound angiogenesis with large scale optoacoustic microscopy. Adv. Sci. 8, 2004226 (2021).

    Article  CAS  Google Scholar 

  154. Gurevich, D. B. et al. Live imaging of wound angiogenesis reveals macrophage orchestrated vessel sprouting and regression. EMBO J. 37, e97786 (2018). This study shows, in translucent zebrafish, how wound angiogenesis is first inhibited by neutrophils and then driven by VEGF signals from pro-inflammatory macrophages, and finally pruned back again after healing is complete by anti-inflammatory macrophages.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Noishiki, C. et al. Live imaging of angiogenesis during cutaneous wound healing in adult zebrafish. Angiogenesis 22, 341–354 (2019).

    Article  PubMed  Google Scholar 

  156. Brown, L. F. et al. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J. Exp. Med. 176, 1375–1379 (1992).

    Article  CAS  PubMed  Google Scholar 

  157. Wietecha, M. S. et al. Sprouty2 downregulates angiogenesis during mouse skin wound healing. Am. J. Physiol. Heart Circ. Physiol. 300, H459–H467 (2011).

    Article  CAS  PubMed  Google Scholar 

  158. Michalczyk, E. R., Chen, L., Maia, M. B. & Dipietro, L. A. A role for low-density lipoprotein receptor-related protein 6 in blood vessel regression in wound healing. Adv. Wound Care 9, 1–8 (2020).

    Article  Google Scholar 

  159. Michalczyk, E. R. et al. Pigment epithelium-derived factor (PEDF) as a regulator of wound angiogenesis. Sci. Rep. 8, 11142 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Minutti, C. M. et al. A macrophage-pericyte axis directs tissue restoration via amphiregulin-induced transforming growth factor beta activation. Immunity 50, 645–654.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Hägerling, R., Pollmann, C., Kremer, L., Andresen, V. & Kiefer, F. Intravital two-photon microscopy of lymphatic vessel development and function using a transgenic Prox1 promoter-directed mOrange2 reporter mouse. Biochem. Soc. Trans. 39, 1674–1681 (2011).

    Article  PubMed  Google Scholar 

  162. Schwager, S. & Detmar, M. Inflammation and lymphatic function. Front. Immunol. 10, 308 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Vaahtomeri, K., Karaman, S., Mäkinen, T. & Alitalo, K. Lymphangiogenesis guidance by paracrine and pericellular factors. Genes Dev. 31, 1615–1634 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Hosono, K., Isonaka, R., Kawakami, T., Narumiya, S. & Majima, M. Signaling of prostaglandin E receptors, EP3 and EP4 facilitates wound healing and lymphangiogenesis with enhanced recruitment of M2 macrophages in mice. PLoS One 11, e0162532 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Kurashige, C. et al. Roles of receptor activity-modifying protein 1 in angiogenesis and lymphangiogenesis during skin wound healing in mice. FASEB J. 28, 1237–1247 (2014).

    Article  CAS  PubMed  Google Scholar 

  166. Huggenberger, R. et al. An important role of lymphatic vessel activation in limiting acute inflammation. Blood 117, 4667–4678 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kataru, R. P. et al. Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 113, 5650–5659 (2009).

    Article  CAS  PubMed  Google Scholar 

  168. Guo, R. et al. Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthritis Rheum. 60, 2666–2676 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Kim, K. E. et al. Role of CD11b+ macrophages in intraperitoneal lipopolysaccharide-induced aberrant lymphangiogenesis and lymphatic function in the diaphragm. Am. J. Pathol. 175, 1733–1745 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Egozi, E. I., Ferreira, A. M., Burns, A. L., Gamelli, R. L. & Dipietro, L. A. Mast cells modulate the inflammatory but not the proliferative response in healing wounds. Wound Repair Regen. 11, 46–54 (2003).

    Article  PubMed  Google Scholar 

  171. Komi, D. E. A., Khomtchouk, K. & Santa Maria, P. L. A review of the contribution of mast cells in wound healing: involved molecular and cellular mechanisms. Clin. Rev. Allergy Immunol. 58, 298–312 (2020).

    Article  CAS  PubMed  Google Scholar 

  172. Weller, K., Foitzik, K., Paus, R., Syska, W. & Maurer, M. Mast cells are required for normal healing of skin wounds in mice. FASEB J. 20, 2366–2368 (2006).

    Article  CAS  PubMed  Google Scholar 

  173. Antsiferova, M. et al. Mast cells are dispensable for normal and activin-promoted wound healing and skin carcinogenesis. J. Immunol. 191, 6147–6155 (2013).

    Article  CAS  PubMed  Google Scholar 

  174. Willenborg, S. et al. Genetic ablation of mast cells redefines the role of mast cells in skin wound healing and bleomycin-induced fibrosis. J. Invest. Dermatol. 134, 2005–2015 (2014).

    Article  CAS  PubMed  Google Scholar 

  175. Joshi, N. et al. Comprehensive characterization of myeloid cells during wound healing in healthy and healing-impaired diabetic mice. Eur. J. Immunol. 50, 1335–1349 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Ribot, J. C., Lopes, N. & Silva-Santos, B. γδ T cells in tissue physiology and surveillance. Nat. Rev. Immunol. 21, 221–232 (2021).

    Article  CAS  PubMed  Google Scholar 

  177. Chodaczek, G., Papanna, V., Zal, M. A. & Zal, T. Body-barrier surveillance by epidermal γδ TCRs. Nat. Immunol. 13, 272–282 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Park, S. et al. Skin-resident immune cells actively coordinate their distribution with epidermal cells during homeostasis. Nat. Cell Biol. 23, 476–484 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Jameson, J. et al. A role for skin γδ T cells in wound repair. Science 296, 747–749 (2002). This was the first study to establish a key role for dendritic epidermal T cells in epidermal wound healing by releasing keratinocyte growth factors that induce hyaluronan production in keratinocytes.

    Article  CAS  PubMed  Google Scholar 

  180. Sharp, L. L., Jameson, J. M., Cauvi, G. & Havran, W. L. Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nat. Immunol. 6, 73–79 (2005).

    Article  CAS  PubMed  Google Scholar 

  181. Toulon, A. et al. A role for human skin-resident T cells in wound healing. J. Exp. Med. 206, 743–750 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Ramirez, K., Witherden, D. A. & Havran, W. L. All hands on DE(T)C: epithelial-resident γδ T cells respond to tissue injury. Cell. Immunol. 296, 57–61 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Jameson, J. M., Cauvi, G., Sharp, L. L., Witherden, D. A. & Havran, W. L. γδ T cell-induced hyaluronan production by epithelial cells regulates inflammation. J. Exp. Med. 201, 1269–1279 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Qu, G. et al. Comparing mouse and human tissue-resident γδ T cells. Front. Immunol. 13, 891687 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Hu, W. et al. Skin γδ T cells and their function in wound healing. Front. Immunol. 13, 875076 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Ho, A. W. & Kupper, T. S. T cells and the skin: from protective immunity to inflammatory skin disorders. Nat. Rev. Immunol. 19, 490–502 (2019).

    Article  CAS  PubMed  Google Scholar 

  187. Boothby, I. C., Cohen, J. N. & Rosenblum, M. D. Regulatory T cells in skin injury: at the crossroads of tolerance and tissue repair. Sci. Immunol. 5, eaaz9631 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Ali, N. et al. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169, 1119–1129.e11 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Sanchez Rodriguez, R. et al. Memory regulatory T cells reside in human skin. J. Clin. Invest. 124, 1027–1036 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Mathur, A. N. et al. Treg-cell control of a CXCL5-IL-17 inflammatory axis promotes hair-follicle-stem-cell differentiation during skin-barrier repair. Immunity 50, 655–667.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Nosbaum, A. et al. Cutting edge: regulatory T cells facilitate cutaneous wound healing. J. Immunol. 196, 2010–2014 (2016).

    Article  CAS  PubMed  Google Scholar 

  192. Kalekar, L. A. et al. Regulatory T cells in skin are uniquely poised to suppress profibrotic immune responses. Sci. Immunol. 4, eaaw2910 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Szabo, P. A., Miron, M. & Farber, D. L. Location, location, location: tissue resident memory T cells in mice and humans. Sci. Immunol. 4, eaas9673 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Khan, T. N., Mooster, J. L., Kilgore, A. M., Osborn, J. F. & Nolz, J. C. Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection. J. Exp. Med. 213, 951–966 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Ariotti, S. et al. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. Science 346, 101–105 (2014).

    Article  CAS  PubMed  Google Scholar 

  196. Schenkel, J. M. et al. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Debes, G. F. & McGettigan, S. E. Skin-associated B cells in health and inflammation. J. Immunol. 202, 1659–1666 (2019).

    Article  CAS  PubMed  Google Scholar 

  198. Oliveira, H. C. et al. B-1 cells modulate the kinetics of wound-healing process in mice. Immunobiology 215, 215–222 (2010).

    Article  CAS  PubMed  Google Scholar 

  199. Iwata, Y. et al. CD19, a response regulator of B lymphocytes, regulates wound healing through hyaluronan-induced TLR4 signaling. Am. J. Pathol. 175, 649–660 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Walker, J. A., Barlow, J. L. & McKenzie, A. N. J. Innate lymphoid cells — how did we miss them? Nat. Rev. Immunol. 13, 75–87 (2013).

    Article  CAS  PubMed  Google Scholar 

  201. Spits, H. et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

    Article  CAS  PubMed  Google Scholar 

  202. Roediger, B. et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat. Immunol. 14, 564–573 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Rak, G. D. et al. IL-33-dependent group 2 innate lymphoid cells promote cutaneous wound healing. J. Invest. Dermatol. 136, 487–496 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Franz, A., Wood, W. & Martin, P. Fat body cells are motile and actively migrate to wounds to drive repair and prevent infection. Dev. Cell 44, 460–470.e3 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Zhang, L.-J. et al. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 347, 67–71 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Souza, C. O. et al. Palmitoleic acid reduces the inflammation in LPS-stimulated macrophages by inhibition of NFκB, independently of PPARs. Clin. Exp. Pharmacol. Physiol. 44, 566–575 (2017).

    Article  CAS  PubMed  Google Scholar 

  207. Camell, C. & Smith, C. W. Dietary oleic acid increases M2 macrophages in the mesenteric adipose tissue. PLoS One 8, e75147 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Vieira, W. A., Sadie-Van Gijsen, H. & Ferris, W. F. Free fatty acid G-protein coupled receptor signaling in M1 skewed white adipose tissue macrophages. Cell. Mol. Life Sci. 73, 3665–3676 (2016).

    Article  CAS  PubMed  Google Scholar 

  209. Schmidt, B. A. & Horsley, V. Intradermal adipocytes mediate fibroblast recruitment during skin wound healing. Development 140, 1517–1527 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Shook, B. A. et al. Dermal adipocyte lipolysis and myofibroblast conversion are required for efficient skin repair. Cell Stem Cell 26, 880–895.e6 (2020). This study provides evidence for adipocytes adjacent to a wound, shedding lipid, which may in part recruit inflammatory cells and then change their fate to become wound myofibroblasts; they may even become motile to move into the wound.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Kalgudde Gopal, S. et al. Wound infiltrating adipocytes are not myofibroblasts. Nat. Commun. 14, 3020 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Plikus, M. V. et al. Regeneration of fat cells from myofibroblasts during wound healing. Science 355, 748–752 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Chadwick, S. L., Yip, C., Ferguson, M. W. J. & Shah, M. Repigmentation of cutaneous scars depends on original wound type. J. Anat. 223, 74–82 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Lévesque, M., Feng, Y., Jones, R. & Martin, P. Inflammation drives wound hyperpigmentation in zebrafish by recruiting pigment cells to sites of tissue damage. Dis. Model. Mech. 6, 508–515 (2013).

    PubMed  Google Scholar 

  215. Han, H. et al. Preferential stimulation of melanocytes by M2 macrophages to produce melanin through vascular endothelial growth factor. Sci. Rep. 12, 6416 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Sun, Q. et al. Dissecting Wnt signaling for melanocyte regulation during wound healing. J. Invest. Dermatol. 138, 1591–1600 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Farkas, J. E. & Monaghan, J. R. A brief history of the study of nerve dependent regeneration. Neurogenesis 4, e1302216 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Harsum, S., Clarke, J. D. W. & Martin, P. A reciprocal relationship between cutaneous nerves and repairing skin wounds in the developing chick embryo. Dev. Biol. 238, 27–39 (2001).

    Article  CAS  PubMed  Google Scholar 

  219. Kishi, K. et al. Mutual dependence of murine fetal cutaneous regeneration and peripheral nerve regeneration. Wound Repair Regen. 14, 91–99 (2006).

    Article  PubMed  Google Scholar 

  220. Fujiwara, T. et al. Direct contact of fibroblasts with neuronal processes promotes differentiation to myofibroblasts and induces contraction of collagen matrix in vitro. Wound Repair Regen. 21, 588–594 (2013).

    Article  PubMed  Google Scholar 

  221. Parfejevs, V. et al. Injury-activated glial cells promote wound healing of the adult skin in mice. Nat. Commun. 9, 236 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Liao, X.-H. & Nguyen, H. Epidermal expression of Lgr6 is dependent on nerve endings and Schwann cells. Exp. Dermatol. 23, 195–198 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Huang, S. et al. Lgr6 marks epidermal stem cells with a nerve-dependent role in wound re-epithelialization. Cell Stem Cell 28, 1582–1596.e6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Brownell, I., Guevara, E., Bai, C. B., Loomis, C. A. & Joyner, A. L. Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells. Cell Stem Cell 8, 552–565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Rasmussen, J. P., Sack, G. S., Martin, S. M. & Sagasti, A. Vertebrate epidermal cells are broad-specificity phagocytes that clear sensory axon debris. J. Neurosci. 35, 559–570 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Rosenberg, A. F., Wolman, M. A., Franzini-Armstrong, C. & Granato, M. In vivo nerve-macrophage interactions following peripheral nerve injury. J. Neurosci. 32, 3898–3909 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. 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 

  228. Reynolds, M. L. & Fitzgerald, M. Long-term sensory hyperinnervation following neonatal skin wounds. J. Comp. Neurol. 358, 487–498 (1995).

    Article  CAS  PubMed  Google Scholar 

  229. Beggs, S. et al. A role for NT-3 in the hyperinnervation of neonatally wounded skin. Pain 153, 2133–2139 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Shen, L. et al. Neurotrophin-3 accelerates wound healing in diabetic mice by promoting a paracrine response in mesenchymal stem cells. Cell Transpl. 22, 1011–1021 (2013).

    Article  Google Scholar 

  231. Deán-Ben, X. L. & Razansky, D. Optoacoustic imaging of the skin. Exp. Dermatol. 30, 1598–1609 (2021).

    Article  PubMed  Google Scholar 

  232. Weavers, H. et al. Systems analysis of the dynamic inflammatory response to tissue damage reveals spatiotemporal properties of the wound attractant gradient. Curr. Biol. 26, 1975–1989 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Turley, J., Chenchiah, I. V., Liverpool, T. B., Weavers, H. & Martin, P. What good is maths in studies of wound healing? iScience 25, 104778 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  234. Peurichard, D. et al. Extra-cellular matrix rigidity may dictate the fate of injury outcome. J. Theor. Biol. 469, 127–136 (2019).

    Article  CAS  PubMed  Google Scholar 

  235. Di Domizio, J. et al. The commensal skin microbiota triggers type I IFN-dependent innate repair responses in injured skin. Nat. Immunol. 21, 1034–1045 (2020).

    Article  PubMed  Google Scholar 

  236. Mascharak, S. et al. Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing. Cell Stem Cell 29, 315–327.e6 (2022). This study is a state-of-the-art demonstration of how multiomics analysis of wound repair tissues can reveal key fibrotic versus regenerative signalling pathways.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Talbott, H. E., Mascharak, S., Griffin, M., Wan, D. C. & Longaker, M. T. Wound healing, fibroblast heterogeneity, and fibrosis. Cell Stem Cell 29, 1161–1180 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Nat. Commun. 12, 1088 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Efremova, M., Vento-Tormo, M., Teichmann, S. A. & Vento-Tormo, R. CellPhoneDB: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes. Nat. Protoc. 15, 1484–1506 (2020).

    Article  CAS  PubMed  Google Scholar 

  240. Li, J. et al. Spatially resolved proteomic map shows that extracellular matrix regulates epidermal growth. Nat. Commun. 13, 4012 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Liu, Z. et al. Integrative small and long RNA omics analysis of human healing and nonhealing wounds discovers cooperating microRNAs as therapeutic targets. eLife 11, e80322 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Labuz, D. R. et al. Targeted multi-omic analysis of human skin tissue identifies alterations of conventional and unconventional T cells associated with burn injury. eLife 12, e82626 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Theocharidis, G. et al. Single cell transcriptomic landscape of diabetic foot ulcers. Nat. Commun. 13, 181 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Li, D. et al. Single-cell analysis reveals major histocompatibility complex II-expressing keratinocytes in pressure ulcers with worse healing outcomes. J. Invest. Dermatol. 142, 705–716 (2022).

    Article  CAS  PubMed  Google Scholar 

  245. Ross, R. & Odland, G. Human wound repair. II. Inflammatory cells, epithelial-mesenchymal interrelations, and fibrogenesis. J. Cell Biol. 39, 152–168 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Odland, G. & Ross, R. Human wound repair. I. Epidermal regeneration. J. Cell Biol. 39, 135–151 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. El Kinani, M. & Duteille, F. In Textbook on Scar Management (eds Téot, L., Mustoe, T. A., Middelkoop, E. & Gauglitz, G. G.) 45-49 (Springer International Publishing, 2020).

  248. Van Baar, M. E. In Textbook on Scar Management (eds Téot, L., Mustoe, T. A., Middelkoop, E. & Gauglitz, G. G.) 37-43 (Springer International Publishing, 2020).

  249. Visscher, P. M. et al. 10 years of GWAS discovery: biology, function, and translation. Am. J. Hum. Genet. 101, 5–22 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Flannick, J. et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat. Genet. 46, 357–363 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Esplin, E. D., Oei, L. & Snyder, M. P. Personalized sequencing and the future of medicine: discovery, diagnosis and defeat of disease. Pharmacogenomics 15, 1771–1790 (2014).

    Article  CAS  PubMed  Google Scholar 

  252. Suwinski, P. et al. Advancing personalized medicine through the application of whole exome sequencing and big data analytics. Front. Genet. 10, 49 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Bosanquet, D. C. et al. Development and validation of a gene expression test to identify hard-to-heal chronic venous leg ulcers. Br. J. Surg. 106, 1035–1042 (2019).

    Article  CAS  PubMed  Google Scholar 

  254. Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Campana, L., Esser, H., Huch, M. & Forbes, S. Liver regeneration and inflammation: from fundamental science to clinical applications. Nat. Rev. Mol. Cell Biol. 22, 608–624 (2021).

    Article  CAS  PubMed  Google Scholar 

  256. Neupane, A. S. & Kubes, P. Imaging reveals novel innate immune responses in lung, liver, and beyond. Immunol. Rev. 306, 244–257 (2022).

    Article  CAS  PubMed  Google Scholar 

  257. Wang, J. & Kubes, P. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell 165, 668–678 (2016).

    Article  CAS  PubMed  Google Scholar 

  258. Ferreira-Gonzalez, S. et al. Senolytic treatment preserves biliary regenerative capacity lost through cellular senescence during cold storage. Sci. Transl. Med. 14, eabj4375 (2022).

    Article  CAS  PubMed  Google Scholar 

  259. Richardson, R. J. Parallels between vertebrate cardiac and cutaneous wound healing and regeneration. NPJ Regen. Med. 3, 21 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  260. Senyo, S. E. et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature 493, 433–436 (2013).

    Article  CAS  PubMed  Google Scholar 

  261. Ali, S. R. et al. Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice. Proc. Natl Acad. Sci. USA 111, 8850–8855 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Wang, X. & Zhou, L. The many roles of macrophages in skeletal muscle injury and repair. Front. Cell Dev. Biol. 10, 952249 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  263. Dhawan, U., Jaffery, H., Salmeron-Sanchez, M. & Dalby, M. J. An ossifying landscape: materials and growth factor strategies for osteogenic signalling and bone regeneration. Curr. Opin. Biotechnol. 73, 355–363 (2022).

    Article  CAS  PubMed  Google Scholar 

  264. Chang, J. et al. Circadian control of the secretory pathway maintains collagen homeostasis. Nat. Cell Biol. 22, 74–86 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Hoyle, N. P. et al. Circadian actin dynamics drive rhythmic fibroblast mobilization during wound healing. Sci. Transl. Med. 9, eaal2774 (2017). This study shows how the circadian clock impacts the rate of fibroblast migration into a wound in mice — being slower in their resting period during the day — and complements this with a clinical review showing how wounds that occur at night heal slower than those that occur during the day.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank members of their lab for support and reading of various sections of this Review, and their funders the Wellcome Trust, the Medical Research Council and The Scar Free Foundation.

Author information

Authors and Affiliations

  1. School of Biochemistry, University of Bristol, Bristol, UK

    Oscar A. Peña & Paul Martin

Authors
  1. Oscar A. Peña
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all stages of writing and revision of the article.

Corresponding authors

Correspondence to Oscar A. Peña or Paul Martin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Molecular Cell Biology thanks Yuval Rinkevich, Sabine Werner and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Adipocyte

A cell that supports the metabolism of surrounding cells and tissues by storing and breaking down triglycerides to release fatty acids.

Anastomose

Connection (sometimes temporary) between sprouting vessels.

Chemotaxis

The directed migration of cells towards a small molecule, chemokine or growth factor cue.

Efferocytosis

A term that is derived from the Latin word efferre (which means ‘to take to the grave’ or ‘to bury’) and describes a process by which dead cells are removed by professional phagocytes.

Eicosanoid

A group of inflammatory lipid mediators derived from arachidonic acid, including lipoxins and prostaglandins.

Epimorphic regeneration

The process whereby some organisms can regrow tissues or organs that completely replicate those that have been lost.

Extravasation

The movement of immune cells from the lumen of a vessel out into the extravascular tissue, generally in response to some inflammatory activator.

Factor XII

A key component of the coagulation cascade activated by exposure to extravascular components, for example, collagen.

GADD45

A DNA demethylase that may have a role in cellular resilience post inflammation.

HMGB1

HMGB1 is released by damaged cells and may act as an attractant for immune cells.

Lipoxins

Lipid mediators that promote inflammation resolution by retarding the recruitment of neutrophils and stimulating efferocytosis.

Macrophages

A later leukocytic arriver; macrophages can exhibit a range of phenotypes or behaviours and orchestrate many activities by other cell lineages in the wound.

Mechanotransduction

A process where mechanical cues are converted into biochemical signals by cells.

Melanocytes

Key cells in the production of melanin, which is transported to neighbouring keratinocytes and protects skin cells from damage by ultraviolet radiation.

Neutrophils

The first type of leukocyte to arrive at a wound; specialized for microbicidal activities.

Osteopontin

Also known as SPP1; is both a transcription factor and a matricular protein implicated in inflammation-mediated scarring.

Platelet degranulation

Enables the regulated release of granules containing various mediators of inflammation, including histamine and several growth factors.

Pruning

Term used to describe the removal of excess vessels (and nerves) after wound repair is complete.

Selectin

Family of cell adhesion molecules with established roles in immune cell extravasation.

Swarming of neutrophils

Cooperative behaviour of neutrophils where positive feedback loops and signal amplification promote massive inflammatory recruitment.

T cells

A group of lymphocytes specialized in adaptative immunity.

Transdifferentiate

Conversion of one cell type or lineage into another.

YAP

Transcription factor component of Hippo pathway signalling.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peña, O.A., Martin, P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00715-1

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41580-024-00715-1

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing