Skip to main content
PMC home page
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2004 May 29;359(1445):777–784. doi: 10.1098/rstb.2004.1466

Wound healing and inflammation: embryos reveal the way to perfect repair.

Michael J Redd 1, Lisa Cooper 1, Will Wood 1, Brian Stramer 1, Paul Martin 1
PMCID: PMC1693361  PMID: 15293805

Abstract

Tissue repair in embryos is rapid, efficient and perfect and does not leave a scar, an ability that is lost as development proceeds. Whereas adult wound keratinocytes crawl forwards over the exposed substratum to close the gap, a wound in the embryonic epidermis is closed by contraction of a rapidly assembled actin purse string. Blocking assembly of this cable in chick and mouse embryos, by drugs or by inactivation of the small GTPase Rho, severely hinders the re-epithelialization process. Live studies of epithelial repair in GFP-actin-expressing Drosophila embryos reveal actin-rich filopodia associated with the cable, and although these protrusions from leading edge cells appear to play little role in epithelial migration, they are essential for final zippering of the wound edges together-inactivation of Cdc42 prevents their assembly and blocks the final adhesion step. This wound re-epithelialization machinery appears to recapitulate that used during naturally occurring morphogenetic episodes as typified by Drosophila dorsal closure. One key difference between embryonic and adult repair, which may explain why one heals perfectly and the other scars, is the presence of an inflammatory response at sites of adult repair where there is none in the embryo. Our studies of repair in the PU. 1 null mouse, which is genetically incapable of raising an inflammatory response, show that inflammation may indeed be partly responsible for scarring, and our genetic studies of inflammation in zebrafish (Danio rerio) larvae suggest routes to identifying gene targets for therapeutically modulating the recruitment of inflammatory cells and thus improving adult healing.

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bloor James W., Kiehart Daniel P. Drosophila RhoA regulates the cytoskeleton and cell-cell adhesion in the developing epidermis. Development. 2002 Jul;129(13):3173–3183. doi: 10.1242/dev.129.13.3173. [DOI] [PubMed] [Google Scholar]
  2. 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. 1996 Nov;135(4):1097–1107. doi: 10.1083/jcb.135.4.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Coussens Lisa M., Werb Zena. Inflammation and cancer. Nature. 2002 Dec 19;420(6917):860–867. doi: 10.1038/nature01322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Desmoulière A., Geinoz A., Gabbiani F., Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993 Jul;122(1):103–111. doi: 10.1083/jcb.122.1.103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Doitsidou Maria, Reichman-Fried Michal, Stebler Jürg, Köprunner Marion, Dörries Julia, Meyer Dirk, Esguerra Camila V., Leung TinChung, Raz Erez. Guidance of primordial germ cell migration by the chemokine SDF-1. Cell. 2002 Nov 27;111(5):647–659. doi: 10.1016/s0092-8674(02)01135-2. [DOI] [PubMed] [Google Scholar]
  6. Farge Emmanuel. Mechanical induction of Twist in the Drosophila foregut/stomodeal primordium. Curr Biol. 2003 Aug 19;13(16):1365–1377. doi: 10.1016/s0960-9822(03)00576-1. [DOI] [PubMed] [Google Scholar]
  7. Grinnell F. Fibroblasts, myofibroblasts, and wound contraction. J Cell Biol. 1994 Feb;124(4):401–404. doi: 10.1083/jcb.124.4.401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Grinnell F. Wound repair, keratinocyte activation and integrin modulation. J Cell Sci. 1992 Jan;101(Pt 1):1–5. doi: 10.1242/jcs.101.1.1. [DOI] [PubMed] [Google Scholar]
  9. Grose Richard, Harris Brett S., Cooper Lisa, Topilko Piotr, Martin Paul. Immediate early genes krox-24 and krox-20 are rapidly up-regulated after wounding in the embryonic and adult mouse. Dev Dyn. 2002 Mar;223(3):371–378. doi: 10.1002/dvdy.10064. [DOI] [PubMed] [Google Scholar]
  10. Harden Nicholas. Signaling pathways directing the movement and fusion of epithelial sheets: lessons from dorsal closure in Drosophila. Differentiation. 2002 Jun;70(4-5):181–203. doi: 10.1046/j.1432-0436.2002.700408.x. [DOI] [PubMed] [Google Scholar]
  11. Heasman Janet. Morpholino oligos: making sense of antisense? Dev Biol. 2002 Mar 15;243(2):209–214. doi: 10.1006/dbio.2001.0565. [DOI] [PubMed] [Google Scholar]
  12. 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. 1994 May;107(Pt 5):1159–1167. doi: 10.1242/jcs.107.5.1159. [DOI] [PubMed] [Google Scholar]
  13. Hutson M. Shane, Tokutake Yoichiro, Chang Ming-Shien, Bloor James W., Venakides Stephanos, Kiehart Daniel P., Edwards Glenn S. Forces for morphogenesis investigated with laser microsurgery and quantitative modeling. Science. 2003 Feb 6;300(5616):145–149. doi: 10.1126/science.1079552. [DOI] [PubMed] [Google Scholar]
  14. Jacinto A., Martinez-Arias A., Martin P. Mechanisms of epithelial fusion and repair. Nat Cell Biol. 2001 May;3(5):E117–E123. doi: 10.1038/35074643. [DOI] [PubMed] [Google Scholar]
  15. Jacinto A., Wood W., Balayo T., Turmaine M., Martinez-Arias A., Martin P. Dynamic actin-based epithelial adhesion and cell matching during Drosophila dorsal closure. Curr Biol. 2000 Nov 16;10(22):1420–1426. doi: 10.1016/s0960-9822(00)00796-x. [DOI] [PubMed] [Google Scholar]
  16. Jacinto Antonio, Wood William, Woolner Sarah, Hiley Charlotte, Turner Laura, Wilson Clive, Martinez-Arias Alfonso, Martin Paul. Dynamic analysis of actin cable function during Drosophila dorsal closure. Curr Biol. 2002 Jul 23;12(14):1245–1250. doi: 10.1016/s0960-9822(02)00955-7. [DOI] [PubMed] [Google Scholar]
  17. Jacinto Antonio, Woolner Sarah, Martin Paul. Dynamic analysis of dorsal closure in Drosophila: from genetics to cell biology. Dev Cell. 2002 Jul;3(1):9–19. doi: 10.1016/s1534-5807(02)00208-3. [DOI] [PubMed] [Google Scholar]
  18. Leibovich S. J., Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975 Jan;78(1):71–100. [PMC free article] [PubMed] [Google Scholar]
  19. Martin P., Dickson M. C., Millan F. A., Akhurst R. J. Rapid induction and clearance of TGF beta 1 is an early response to wounding in the mouse embryo. Dev Genet. 1993;14(3):225–238. doi: 10.1002/dvg.1020140309. [DOI] [PubMed] [Google Scholar]
  20. Martin P., Lewis J. Actin cables and epidermal movement in embryonic wound healing. Nature. 1992 Nov 12;360(6400):179–183. doi: 10.1038/360179a0. [DOI] [PubMed] [Google Scholar]
  21. 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. 1992 Sep;38(3):209–215. doi: 10.1016/0925-4773(92)90054-n. [DOI] [PubMed] [Google Scholar]
  22. Martin P. Wound healing--aiming for perfect skin regeneration. Science. 1997 Apr 4;276(5309):75–81. doi: 10.1126/science.276.5309.75. [DOI] [PubMed] [Google Scholar]
  23. Martin Paul, D'Souza Deana, Martin Julie, Grose Richard, Cooper Lisa, Maki Rich, McKercher Scott R. Wound healing in the PU.1 null mouse--tissue repair is not dependent on inflammatory cells. Curr Biol. 2003 Jul 1;13(13):1122–1128. doi: 10.1016/s0960-9822(03)00396-8. [DOI] [PubMed] [Google Scholar]
  24. Mateo R. B., Reichner J. S., Albina J. E. Interleukin-6 activity in wounds. Am J Physiol. 1994 Jun;266(6 Pt 2):R1840–R1844. doi: 10.1152/ajpregu.1994.266.6.R1840. [DOI] [PubMed] [Google Scholar]
  25. McCluskey J., Hopkinson-Woolley J., Luke B., Martin P. A study of wound healing in the E11.5 mouse embryo by light and electron microscopy. Tissue Cell. 1993;25(2):173–181. doi: 10.1016/0040-8166(93)90017-f. [DOI] [PubMed] [Google Scholar]
  26. McCluskey J., Martin P. Analysis of the tissue movements of embryonic wound healing--DiI studies in the limb bud stage mouse embryo. Dev Biol. 1995 Jul;170(1):102–114. doi: 10.1006/dbio.1995.1199. [DOI] [PubMed] [Google Scholar]
  27. McKercher S. R., Torbett B. E., Anderson K. L., Henkel G. W., Vestal D. J., Baribault H., Klemsz M., Feeney A. J., Wu G. E., Paige C. J. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J. 1996 Oct 15;15(20):5647–5658. [PMC free article] [PubMed] [Google Scholar]
  28. Morris L., Graham C. F., Gordon S. Macrophages in haemopoietic and other tissues of the developing mouse detected by the monoclonal antibody F4/80. Development. 1991 Jun;112(2):517–526. doi: 10.1242/dev.112.2.517. [DOI] [PubMed] [Google Scholar]
  29. Raich W. B., Agbunag C., Hardin J. Rapid epithelial-sheet sealing in the Caenorhabditis elegans embryo requires cadherin-dependent filopodial priming. Curr Biol. 1999 Oct 21;9(20):1139–1146. doi: 10.1016/S0960-9822(00)80015-9. [DOI] [PubMed] [Google Scholar]
  30. Rämet Mika, Lanot René, Zachary Daniel, Manfruelli Pascal. JNK signaling pathway is required for efficient wound healing in Drosophila. Dev Biol. 2002 Jan 1;241(1):145–156. doi: 10.1006/dbio.2001.0502. [DOI] [PubMed] [Google Scholar]
  31. Shah M., Foreman D. M., Ferguson M. W. Control of scarring in adult wounds by neutralising antibody to transforming growth factor beta. Lancet. 1992 Jan 25;339(8787):213–214. doi: 10.1016/0140-6736(92)90009-r. [DOI] [PubMed] [Google Scholar]
  32. Shah M., Foreman D. M., Ferguson M. W. Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci. 1995 Mar;108(Pt 3):985–1002. doi: 10.1242/jcs.108.3.985. [DOI] [PubMed] [Google Scholar]
  33. Shah M., Foreman D. M., Ferguson M. W. Neutralising antibody to TGF-beta 1,2 reduces cutaneous scarring in adult rodents. J Cell Sci. 1994 May;107(Pt 5):1137–1157. doi: 10.1242/jcs.107.5.1137. [DOI] [PubMed] [Google Scholar]
  34. Simske J. S., Hardin J. Getting into shape: epidermal morphogenesis in Caenorhabditis elegans embryos. Bioessays. 2001 Jan;23(1):12–23. doi: 10.1002/1521-1878(200101)23:1<12::AID-BIES1003>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  35. Tanino Yoshinori, Makita Hironi, Miyamoto Kenji, Betsuyaku Tomoko, Ohtsuka Yoshinori, Nishihira Jun, Nishimura Masaharu. Role of macrophage migration inhibitory factor in bleomycin-induced lung injury and fibrosis in mice. Am J Physiol Lung Cell Mol Physiol. 2002 Jul;283(1):L156–L162. doi: 10.1152/ajplung.00155.2001. [DOI] [PubMed] [Google Scholar]
  36. Taubes Gary. Cardiovascular disease. Does inflammation cut to the heart of the matter? Science. 2002 Apr 12;296(5566):242–245. doi: 10.1126/science.296.5566.242. [DOI] [PubMed] [Google Scholar]
  37. Vasioukhin V., Bauer C., Yin M., Fuchs E. Directed actin polymerization is the driving force for epithelial cell-cell adhesion. Cell. 2000 Jan 21;100(2):209–219. doi: 10.1016/s0092-8674(00)81559-7. [DOI] [PubMed] [Google Scholar]
  38. Watts D. A., Satsangi J. The genetic jigsaw of inflammatory bowel disease. Gut. 2002 May;50 (Suppl 3):III31–III36. doi: 10.1136/gut.50.suppl_3.iii31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Werner Sabine, Grose Richard. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003 Jul;83(3):835–870. doi: 10.1152/physrev.2003.83.3.835. [DOI] [PubMed] [Google Scholar]
  40. Whitby D. J., Ferguson M. W. Immunohistochemical localization of growth factors in fetal wound healing. Dev Biol. 1991 Sep;147(1):207–215. doi: 10.1016/s0012-1606(05)80018-1. [DOI] [PubMed] [Google Scholar]
  41. Wood William, Jacinto Antonio, Grose Richard, Woolner Sarah, Gale Jonathan, Wilson Clive, Martin Paul. Wound healing recapitulates morphogenesis in Drosophila embryos. Nat Cell Biol. 2002 Nov;4(11):907–912. doi: 10.1038/ncb875. [DOI] [PubMed] [Google Scholar]
  42. Young P. E., Richman A. M., Ketchum A. S., Kiehart D. P. Morphogenesis in Drosophila requires nonmuscle myosin heavy chain function. Genes Dev. 1993 Jan;7(1):29–41. doi: 10.1101/gad.7.1.29. [DOI] [PubMed] [Google Scholar]
  43. Zenz Rainer, Scheuch Harald, Martin Paul, Frank Carsten, Eferl Robert, Kenner Lukas, Sibilia Maria, Wagner Erwin F. c-Jun regulates eyelid closure and skin tumor development through EGFR signaling. Dev Cell. 2003 Jun;4(6):879–889. doi: 10.1016/s1534-5807(03)00161-8. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES