Skip to main content
Log in

Wound-healing studies in transgenic and knockout mice

  • Review
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

Injury to the skin initiates a cascade of events including inflammation, new tissue formation, and tissue remodeling, that finally lead to at least partial reconstruction of the original tissue. Historically, animal models of repair have taught us much about how this repair process is orchestrated and, over recent years, the use of genetically modified mice has helped define the roles of many key molecules. Aside from conventional knockout technology, many ingenious approaches have been adopted, allowing researchers to circumvent such problems as embryonic lethality, or to affect gene function in a tissue-or temporal-specific manner. Together, these studies provide us with a growing source of information describing, to date, the in vivo function of nearly 100 proteins in the context of wound repair.

This article focuses on the studies in which genetically modified mouse models have helped elucidate the roles that many soluble mediators play during wound repair, encompassing the fibroblast growth factor (FGF) and transforming growth factor-β (TGF-β) families and also data on cytokines and chemokines. Finally, we include a table summarizing all of the currently published data in this rapidly growing field. For a regularly updated web archive of studies, we have constructed a Compendium of Published Wound Healing Studies on Genetically Modified Mice which is available at http://icbxs.ethz.ch/members/grose/woundtransgenic/home.html.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Clark, R. A. F. (1996) Wound repair: Overview and general considerations, in The Molecular and Cellular Biology of Wound Repair, 2nd ed. (Clark, R. A. F., ed.) Plenum, New York, pp. 3–50.

    Google Scholar 

  2. Ornitz, D. M. and Itoph, N. (2001) Fibroblast growth factors. Genome Biol. 2, 3005.1–3005.12.

    Article  Google Scholar 

  3. Werner, S. (1998) The role of fibroblast growth factors in skin morphogenesis and wound repair, in Epithelial Morphogenesis in Development and Disease (Birchmeier, C. and Birchmeier, W., eds.), Harwood Academic, GMBH, Chur, Switzerland, p. 233.

    Google Scholar 

  4. Johnson, D. E. and Williams, L. T. (1993) Structural and functional diversity in the FGF receptor multigene family. Adv. Cancer Res. 60, 1–41.

    PubMed  CAS  Google Scholar 

  5. Rosenquist, T. A. and Martin, G. R. (1996) Fibroblast growth factor signalling in the hair growth cycle: expression of the fibroblast growth factor receptor and ligand genes in the murine hair follicle. Dev. Dyn. 205, 379–386.

    Article  PubMed  CAS  Google Scholar 

  6. Abraham, L. A. and Klagsbrun, M. (1996) Modulation of wound repair by members of the fibroblast growth factor family, in The Molecular and Cellular Biology of Wound Repair, 2nd ed. (Clark, R. A. F., ed.), Plenum, New York, pp. 195–248.

    Google Scholar 

  7. Miki, T., Bottaro, D. P., Fleming, T. P., Smith, C. L., Burgess, W. H., Chan, A. M., and Aaronson, S. A. (1992) Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc. Natl. Acad. Sci. USA 89, 246–250.

    Article  PubMed  CAS  Google Scholar 

  8. Werner, S., Peters, K. G., Longaker, M. T., Fuller-Pace, F., Banda, M., and Williams, L. T. (1992) Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc. Natl. Acad. Sci. USA 89, 6896–6900.

    Article  PubMed  CAS  Google Scholar 

  9. Marchese, C., Chedid, M., Dirsch, O. R., Csaky, K. G., Santanelli, F., Latini, C., LaRochelle, W. J., Torrisi, M. R., and Aaronson, S. A. (1995) Modulation of keratinocyte growth factor and its receptor in re-epithelialising human skin. J. Exp. Med. 182, 1369–1376.

    Article  PubMed  CAS  Google Scholar 

  10. Ueno, H., Colbert, H., Escobedo, J. A., and Williams, L. T. (1991) Inhibition of PDGF b-receptor by co-expression of a truncated receptor. Science 252, 844–848.

    Article  PubMed  CAS  Google Scholar 

  11. Honegger, A. M., Schmidt, A., Ullrich, A., and Schlessinger, J. (1990) Evidence for epidermal growth factor (EGF)-induced intermolecular autophosphorylation of the EGF receptors in living cells. Mol. Cell Biol. 10, 4035–4044.

    PubMed  CAS  Google Scholar 

  12. Kashles, O., Yarden, Y., Fischer, R., Ullrich, A., and Schlessinger, J. (1991) A dominant negative mutation suppresses the function of normal epidermal growth factor receptors by heterodimerisation. Mol. Cell Biol. 11, 1454–1463.

    PubMed  CAS  Google Scholar 

  13. Mathieu, M., Chatelain, E., Ornitz, D., Bresnick, J., Mason, I., Kiefer, P., and Dickson, C. (1995) Receptor binding and mitogenic properties of mouse fibroblast growth factor 3: modulation of response by heparin. J. Biol. Chem. 41, 24, 197–24,203.

    Google Scholar 

  14. Yamasaki, M., Miyake, A., Tagashira, S., and Itoh, N. (1996) Structure and expression of the rat mRNA encoding a novel member of the fibroblast growth factor family. J. Biol. Chem. 271, 15,918–15,921.

    CAS  Google Scholar 

  15. Werner, S., Smola, H., Liao, X., Longaker, M. T., Krieg, T., Hofschneider, P. H., and Williams, L. T. (1994) The function of KGF in epithelial morphogenesis and wound re-epithelialisation. Science 266, 819–822.

    Article  PubMed  CAS  Google Scholar 

  16. Guo, L., Degenstein, L., and Fuchs, E. (1996) Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev. 10, 165–175.

    Article  PubMed  CAS  Google Scholar 

  17. Beer, H. D., Florence, C., Dammeier, J., McGuire, L., Werner, S., and Duan, D. R. (1997) Mouse fibroblast growth factor 10: cDNA cloning, protein characterization, and regulation of mRNA expression. Oncogene 15, 2211–2218.

    Article  PubMed  CAS  Google Scholar 

  18. Barrandon, Y. and Green, H. (1987) Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-a and epidermal growth factor. Cell 50, 1131–1137.

    Article  PubMed  CAS  Google Scholar 

  19. Schultz, G. S., White, M., Mitchell, R., Brown, G., Lynch, J., Twardzik, D. R., and Todaro, G. J. (1987) Epithelial wound healing enhanced by transforming growth factor-a and vaccinia growth factor. Science 235, 350–352.

    Article  PubMed  CAS  Google Scholar 

  20. Mann, G. B., Fowler, K. J., Gabriel, A., Nice, E. C., Williams, R. L., and Dunn, A. R. (1993) Mice with a null mutation of the TGFa gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation. Cell 73, 249–261.

    Article  PubMed  CAS  Google Scholar 

  21. Luetteke, N. C., Qiu, T. H., Peiffer, R. L., Oliver, P., Smithies, O., and Lee, D. C. (1993) TGFa deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice. Cell 73, 263–278.

    Article  PubMed  CAS  Google Scholar 

  22. Marikovsky, M., Breuing, K., Liu, P. Y., Eriksson, E., Higashiyama, S., Farber, P., Abraham, J., and Klagsbrun, M. (1993) Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury. Proc. Natl. Acad. Sci. USA 90, 3889–3893.

    Article  PubMed  CAS  Google Scholar 

  23. Sibilia, M. and Wagner, E. F. (1995) Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–238.

    Article  PubMed  CAS  Google Scholar 

  24. Miettinen, P. J., Berger, J. E., Meneses, J., Phung, Y., Pedersen, R. A., Werb, Z., and Derynck, R. (1995) Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337–341.

    Article  PubMed  CAS  Google Scholar 

  25. Murillas, R., Larcher, F., Conti, C. J., Santos, M., Ullrich, A., and Jorcano, J. L. (1995) Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure. EMBO J. 14, 5216–5223.

    PubMed  CAS  Google Scholar 

  26. Bikfalvi, A., Klein, S., Pintucci, G., and Rifkin, D. B. (1997) Biological roles of fibroblast growth factor-2. Endocr. Rev. 18, 26–45.

    Article  PubMed  CAS  Google Scholar 

  27. Ortega, S., Ittmann, M., Tsang, S. H., Ehrlich, M., and Basilico, C. (1998) Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc. Natl. Acad. Sci. USA 95, 5672–5677.

    Article  PubMed  CAS  Google Scholar 

  28. Gibran, N. S., Isik, F. F., Heimbach, D. M., and Gordon, D. (1994) Basic fibroblast growth factor in the early human burn wound. J. Surg. Res. 56, 226–234.

    Article  PubMed  CAS  Google Scholar 

  29. McGee, G. S., Davidson, J. M., Buckley, A., Sommer, A., Woodward, S. C., Aquino, A. M., Barbour, R., and Demetriou, A. A. (1988) Recombinant basic fibroblast growth factor accelerates wound healing. J. Surg. Res. 45, 145–153.

    Article  PubMed  CAS  Google Scholar 

  30. Hebda, P. A., Klingbeil, C. K., Abraham, J. A., and Fiddes, J. C. (1990) Basic fibroblast growth factor stimulation of epidermal wound healing in pigs. J. Invest. Dermatol. 95, 626–631.

    Article  PubMed  CAS  Google Scholar 

  31. Tsuboi, R. and Rifkin, D. B. (1990) Recombinant basic fibroblast growth factor stimulates wound healing in healing-impaired db/db mice. J. Exp. Med. 172, 245–251.

    Article  PubMed  CAS  Google Scholar 

  32. Broadley, K. N., Aquino, A. M., Woodward, S. C., Buckley-Sturrock, A., Sato, Y., Rifkin, D. B., and Davidson, J. M. (1989) Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair. Lab. Invest. 61, 571–575.

    PubMed  CAS  Google Scholar 

  33. Massagué, J. (1990) The transforming growth factor-b family. Annu. Rev. Cell Biol. 6, 597–641.

    Article  PubMed  Google Scholar 

  34. Massague, J. and Wotton, D. (2000) Transcriptional control by the TGF-beta/Smad signaling system. EMBO J. 19, 1745–1754.

    Article  PubMed  CAS  Google Scholar 

  35. Roberts, A. B. and Sporn, M. B. (2001) Transforming growth factor-β, in The Molecular and Cellular Biology of Wound Repair, 2nd ed. (Clark, R. A. F., ed.), Plenum, New York, pp. 275–308.

    Google Scholar 

  36. Levine, J. H., Moses, H. L., Gold, L. I., and Nanney, L. B. (1993) Spatial and temporal patterns of immunoreactive TGF-β1, β2, β3 during excisional wound repair. Am. J. Pathol. 143, 368–380.

    PubMed  CAS  Google Scholar 

  37. Frank, S., Madlener, M., and Werner, S. (1996) Transforming growth factors β1, β2, and β3 and their receptors are differentially regulated during normal and impaired wound healing. J. Biol. Chem. 271, 10,188–10,193.

    Google Scholar 

  38. Shah, M., Foreman, D. M., and Ferguson, M. W. J. (1994) Neutralising antibody to TGF-β1,2 reduces cutaneous scarring in adult rodents. J. Cell Sci. 107, 1137–1157.

    PubMed  CAS  Google Scholar 

  39. Shah, M., Foreman, D. M., and Ferguson, M. W. J. (1995) Neutralisation of TGF-b1 and TGF-b2 or exogenous addition of TGF-β3 to cutaneous rat wounds reduces scarring. J. Cell Sci. 108, 985–1002.

    PubMed  CAS  Google Scholar 

  40. Brown, R. L., Ormsby, I., Doetschman, T. C., and Greenhalgh, D. G. (1995) Wound healing in the transforming growth factor-b1-deficient mouse. Wound Rep. Reg. 3, 25–36.

    Article  CAS  Google Scholar 

  41. Shull, M. M., Ormsby, I., Kier, A. B., Pawlowski, S., Diebold, R. J., Yin, M., Allen, R., Sidman, C., Proetzel, G., Calvin, D., Annunziata, N., and Doetschman, T. (1992) Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699.

    Article  PubMed  CAS  Google Scholar 

  42. Kulkarni, A. B., Huh, C.-G., Becker, D., Geiser, A., Lyght, M., Flanders, K. C., Roberts, A. B., Sporn, M. B., Ward, J. M., and Karlsson, S. (1993) Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770–774.

    Article  PubMed  CAS  Google Scholar 

  43. Letterio, J. J., Geiser, A. G., Kulkarni, A. B, Roche, N. S., Sporn, M. B., and Roberts, A. B. (1994) Maternal rescue of transforming growth factor-β1 null mice. Science 264, 1936–1938.

    Article  PubMed  CAS  Google Scholar 

  44. Greenhalgh, D. G. and Gamelli, R. L. (1987) Is impaired wound healing caused by infection or nutritional depletion? Surgery 102, 306–312.

    PubMed  CAS  Google Scholar 

  45. Reed, B. R. and Clark, R. A. (1985) Cutaneous tissue repair: practical implications of current knowledge. II. J. Am. Acad. Dermatol. 13, 919–941.

    Article  PubMed  CAS  Google Scholar 

  46. Crowe, M. J., Doetschman, T., and Greenhalgh, D. G. (2000) Delayed wound healing in immunodeficient TGF-β 1 knockout mice. J. Invest. Dermatol. 115, 3–11.

    Article  PubMed  CAS  Google Scholar 

  47. Shah, M., Revis, D., Herrick, S., Baillie, R., Thorgeirson, S., Ferguson, M., and Roberts, A. (1999) Role of elevated plasma transforming growth factor-β1 levels in wound healing. Am. J. Pathol. 154, 1115–1124.

    PubMed  CAS  Google Scholar 

  48. Massague, J. (1998) TGF-β signal transduction. Annu. Rev. Biochem. 67, 753–791.

    Article  PubMed  CAS  Google Scholar 

  49. Derynck, R., Zhang, Y., and Feng, X. H. (1998) Smads: transcriptional activators of TGF-β responses. Cell 95, 737–740.

    Article  PubMed  CAS  Google Scholar 

  50. Ashcroft, G. S. and Roberts, A. B. (2000) Loss of Smad3 modulates wound healing. Cytokine Growth Factor Rev. 11, 125–131.

    Article  PubMed  CAS  Google Scholar 

  51. Christian, J. L. and Nakayama, T. (1999) Can’t get no SMADisfaction: Smad proteins as positive and negative regulators of TGF-beta family signals. Bioessays 21, 382–390.

    Article  PubMed  CAS  Google Scholar 

  52. Weinstein, M., Yang, X., Li, C., Xu, X., Gotay, J., and Deng, C. X. (1998) Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor smad2. Proc. Natl. Acad. Sci. USA 95, 9378–9383.

    Article  PubMed  CAS  Google Scholar 

  53. Yang, X., Castilla, L. H., Xu, X., Li, C., Gotay, J., Weinstein, M., Liu, P. P., and Deng, C. X. (1999) Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5. Development 126, 1571–1580.

    PubMed  CAS  Google Scholar 

  54. Ashcroft, G. S., Yang, X., Glick, A. B., Weinstein, M., Letterio, J. L., Mizel, D. E., Anzano, M., Greenwell-Wild, T., Wahl, S. M., Deng, C., and Roberts, A. B. (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat. Cell Biol. 1, 260–266.

    Article  PubMed  CAS  Google Scholar 

  55. Hocevar, B. A., Brown T. L., and Howe, P. H. (1999) TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J. 18, 1345–1356.

    Article  PubMed  CAS  Google Scholar 

  56. Matzuk, M. M., Kumar, T. R., Vassalli, A., Bickenbach, J. R., Roop, D. R., Jaenisch, R., and Bradley, A. (1995) Functional analysis of activins during mammalian development. Nature 374, 354–356.

    Article  PubMed  CAS  Google Scholar 

  57. Matzuk, M. M., Lu, N., Vogel, H., Sellheyer, K., Roop, D. R., and Bradley, A. (1995) Multiple defects and perinatal death in mice deficient in follistatin. Nature 374, 360–363.

    Article  PubMed  CAS  Google Scholar 

  58. Hübner, G., Hu, Q., Smola, H., and Werner, S. (1996) Strong induction of activin expression after injury suggests an important role of activin in wound repair. Dev. Biol. 173, 490–498.

    Article  PubMed  Google Scholar 

  59. Munz, B., Smola, H., Engelhardt, F., Bleuel, K., Brauchle, M., Lein, I., Evans, L. W., Huylebroeck, D., Balling, R., and Werner, S. (1999) Overexpression of activin A in the skin of transgenic mice reveals new activities of activin in epidermal morphogenesis, dermal fibrosis and wound repair. EMBO J. 18, 5205–5215.

    Article  PubMed  CAS  Google Scholar 

  60. Lyons, K. M., Pelton, R. W., and Hogan, B. L. (1989) Patterns of expression of murine Vgr-1 and BMP-2a RNA suggest that transforming growth factor-beta-like genes coordinately regulate aspects of embryonic development. Genes Dev. 3, 1657–1668.

    Article  PubMed  CAS  Google Scholar 

  61. Blessing, M., Schirmacher, P., and Kaiser, S. (1996) Overexpression of bone morphogenetic protein-6 (BMP-6) in the epidermis of transgenic mice: inhibition or stimulation of proliferation depending on the pattern of transgene expression and formation of psoriatic lesions. J. Cell Biol. 135, 227–239.

    Article  PubMed  CAS  Google Scholar 

  62. Kaiser, S., Schirmacher, P., Philipp, A., Protschka, M., Moll, I., Nicol, K., and Blessing, M. (1998) Induction of bone morphogenetic protein-6 in skin wounds: delayed reepitheliazation and scar formation in BMP-6 overexpressing transgenic mice. J. Invest. Dermatol. 111, 1145–1152.

    Article  PubMed  CAS  Google Scholar 

  63. Paquet, P. and Pierard, G. E. (1996) Interleukin-6 and the skin. Int. Arch. Allergy Immunol. 109, 308–317.

    Article  PubMed  CAS  Google Scholar 

  64. Sato, M., Sawamura, D., Ina, S., Yaguchi, T., Hanada, K., and Hashimoto, I. (1999) In vivo introduction of the interleukin 6 gene into human keratinocytes: induction of epidermal proliferation by the fully spliced form of interleukin 6, but not by the alternatively spliced form. Arch. Dermatol. Res. 291, 400–404.

    Article  PubMed  CAS  Google Scholar 

  65. Grossman, R. M., Krueger, J., Yourish, D., Granelli-Piperno, A., Murphy D. P., May, L. T., Kupper, T. S., Sehgal, P. B., and Gottlieb, A. B. (1989) Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc. Natl. Acad. Sci. USA 86, 6367–6371.

    Article  PubMed  CAS  Google Scholar 

  66. Gallucci, R. M., Simeonova, P. P., Matheson, J. M., Kommineni, C., Guriel, J. L., Sugawara, T., and Luster, M. I. (2000) Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB J. 14, 2525–2531.

    Article  PubMed  CAS  Google Scholar 

  67. Bromberg, J. (2001) Activation of STAT proteins and growth control. Bioessays 23, 161–169.

    Article  PubMed  CAS  Google Scholar 

  68. Takeda, K., Noguchi, K., Shi, W., Tanaka, T., Matsumoto, M., Yoshida, N., Kishimoto, T., and Akira, S. (1997) Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. Acad. Sci. USA 94, 3801–3804.

    Article  PubMed  CAS  Google Scholar 

  69. Sano, S., Itami, S., Takeda, K., Tarutani, M., Yamaguchi, Y., Miura, H., Yoshikawa, K., Akira, S., and Takeda, J. (1999) Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J. 18, 4657–4668.

    Article  PubMed  CAS  Google Scholar 

  70. Devalaraja, M. N. and Richmond, A. (1999) Multiple chemotactic factors: fine control or redundancy? Trends Pharmacol. Sci. 20, 151–156.

    Article  PubMed  CAS  Google Scholar 

  71. Engelhardt, E., Toksoy, A., Goebeler, M., Debus, S., Brocker, E. B., and Gillitzer, R. (1998) Chemokines IL-8, GROalpha, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. Am. J. Pathol. 153, 1849–1860.

    PubMed  CAS  Google Scholar 

  72. Luster, A. D., Cardiff, R. D., MacLean, J. A., Crowe, K., and Granstein, R. D. (1998) Delayed wound healing and disorganized neovascularization in transgenic mice expressing the IP-10 chemokine. Proc. Assoc. Am. Physicians 110, 183–196.

    PubMed  CAS  Google Scholar 

  73. Fivenson, D. P., Faria, D. T., Nickoloff, B. J., Poverini, P. J., Kunkel, S., Burdick, M., and Streiter, R. M. (1997) Chemokine and inflammatory cytokine changes during chronic wound healing. Wound Rep. Reg. 5, 310–322.

    Article  CAS  Google Scholar 

  74. Cacalano, G., Lee, J., Kikly, K., Ryan, A. M., Pitts-Meek, S., Hultgren, B., Wood, W. I., and Moore, M. W. (1994) Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog. Science 265, 682–684.

    Article  PubMed  CAS  Google Scholar 

  75. Devalaraja, R. M., Nanney, L. B., Qian, Q., Du, J., Yu, Y., Devalaraja, M. N., and Richmond, A. (2000) Delayed wound healing in CXCR2 knockout mice. J. Invest. Dermatol. 115, 234–244.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  77. Liechty, K. W., Kim, H. B., Adzick, N. S., and Crombleholme, T. M. (2000) Fetal wound repair results in scar formation in interleukin-10-deficient mice in a syngeneic murine model of scarless fetal wound repair. J. Pediatr. Surg. 35, 866–872; discussion: 872,873.

    Article  PubMed  CAS  Google Scholar 

  78. Eckes, B., Colucci-Guyon, E., Smola, H., Nodder, S., Babinet, C., Krieg, T., and Martin, P. (2000) Impaired wound healing in embryonic and adult mice lacking vimentin. J. Cell Sci. 113, 2455–2462.

    PubMed  CAS  Google Scholar 

  79. McCluskey, J. and Martin, P. (1995) Analysis of the tissue movements of embryonic wound healing-DiI studies in the limb bud stage mouse embryo. Dev. Biol. 170, 102–114.

    Article  PubMed  CAS  Google Scholar 

  80. Brock, J., McCluskey, J., Baribault, H., and Martin, P. (1996) Perfect wound healing in the keratin 8 deficient mouse embryo. Cell. Motil. Cytoskel. 35, 358–366.

    Article  CAS  Google Scholar 

  81. Rajewsky, K., Gu, H., Kuhn, R., Betz, U. A., Muller, W., Roes, J., and Schwenk, F. (1996) Conditional gene targeting. J. Clin. Invest. 98, 600–603.

    PubMed  CAS  Google Scholar 

  82. Indra, A. K., Warot, X., Brocard, J., Bornert, J. M., Xiao, J. H., Chambon, P., and Metzger, D. (1999) Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen- inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Res. 27, 4324–4327.

    Article  PubMed  CAS  Google Scholar 

  83. Vasioukhin, V., Degenstein, L., Wise, B., and Fuchs, E. (1999) The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc. Natl. Acad. Sci. USA 96, 8551–8556.

    Article  PubMed  CAS  Google Scholar 

  84. Wang, X. J., Liefer, K. M., Tsai, S., O’Malley, B. W., and Roop, D. R. (1999) Development of gene-switch transgenic mice that inducibly express transforming growth factor beta1 in the epidermis. Proc. Natl. Acad. Sci. USA 96, 8483–8488.

    Article  PubMed  CAS  Google Scholar 

  85. Guo, L., Degenstein, L., Dowling, J., Yu, Q.-C., Wollman, R., Perman, B., and Fuchs, E. (1995) Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration. Cell 81, 233–243.

    Article  PubMed  CAS  Google Scholar 

  86. Abbott, R. E., Corral, C. J., MacIvor, D. M., Lin, X., Ley, T. J., and Mustoe, T. A. (1998) Augmented inflammatory responses and altered wound healing in cathepsin G-deficient mice. Arch. Surg. 133, 1002–1006.

    Article  PubMed  CAS  Google Scholar 

  87. Kaya, G., Rodriguez, I., Jorcano, J. L., Vassalli, P., and Stamenkovic, I. (1997) Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation. Genes Dev. 11, 996–1007.

    Article  PubMed  CAS  Google Scholar 

  88. Hansen, L. A., Alexander, N., Hogan, M. E., Sundberg, J. P., Dlugosz, A., Threadgill, D. W., Magnuson, T., and Yuspa, S. H. (1997) Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development. Am. J. Pathol. 150, 1959–1975.

    PubMed  CAS  Google Scholar 

  89. Bugge, T. H., Kombrinck, K. W., Flick, M. J., Daugherty, C. C., Danton, M. J., and Degen, J. L. (1996) Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell 87, 709–719.

    Article  PubMed  CAS  Google Scholar 

  90. Bezerra, J. A., Carrick, T. L., Degen, J. L., Witte, D., and Degen, S. J. F. (1998) Biological effects of targeted inactivation of hepatocyte growth factor-like protein in mice. J. Clin. Invest. 101, 1175–1183.

    PubMed  CAS  Google Scholar 

  91. Huang, X., Griffiths, M., Wu, J., Farese, R. V. Jr., and Sheppard, D. (2000) Normal development, wound healing, and adenovirus susceptibility in beta5-deficient mice. Mol. Cell. Biol. 20, 755–759.

    Article  PubMed  CAS  Google Scholar 

  92. Wojcik, S. M., Bundman, D. S., and Roop, D. R. (2000) Delayed wound healing in keratin 6a knockout mice. Mol. Cell. Biol. 20, 5248–5255.

    Article  PubMed  CAS  Google Scholar 

  93. Di Colandrea, T., Wang, L., Wille, J., D’Armiento, J., and Chada, K. K. (1998) Epidermal expression of collagenase delays wound-healing in transgenic mice. J. Invest. Dermatol. 111, 1029–1033.

    Article  PubMed  Google Scholar 

  94. Bullard, K. M., Lund, L., Mudgett, J. S., Mellin, T. N., Hunt, T. K., Murphy, B., Ronan, J., Werb, Z., and Banda, M. J. (1999) Impaired wound contraction in stromelysin-1-deficient mice. Ann. Surg. 230, 260–265.

    Article  PubMed  CAS  Google Scholar 

  95. Atit, R. P., Crowe, M. J., Greenhalgh, D. G., Wenstrup, R. J., and Ratner, N. (1999) The Nf1 tumor suppressor regulates mouse skin wound healing, fibroblast proliferation, and collagen deposited by fibroblasts. J. Invest. Dermatol. 112, 835–842.

    Article  PubMed  CAS  Google Scholar 

  96. Lee, P. C., Salyapongse, A. N., Bragdon, G. A., Shears, L. L. 2nd, Watkins, S. C., Edington, H. D., and Billiar, T. R. (1999) Impaired wound healing and angiogenesis in eNOS-deficient mice. Am. J. Physiol. 277, H1600-H1608.

    PubMed  CAS  Google Scholar 

  97. Yamasaki, K., Edington, H. D., McClosky, C., Tzeng, E., Lizonova, A., Kovesdi, I., Steed, D. L., and Billiar, T. R. R. (1998) Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J. Clin. Invest. 101, 967–971.

    PubMed  CAS  Google Scholar 

  98. Liaw, L., Birk, D. E., Ballas, C. B., Whitsitt, J. S., Davidson, J. M., and Hogan, B. L. (1998) Altered wound healing in mice lacking a functional osteopontin gene (sppl). J. Clin. Invest. 101, 1468–1478.

    PubMed  CAS  Google Scholar 

  99. Dougherty, K. M., Pearson, J. M., Yang, A. Y., Westrick, R. J., Baker, M. S., and Ginsburg, D. (1999) The plasminogen activator inhibitor-2 gene is not required for normal murine development or survival. Proc. Natl. Acad. Sci. USA 96, 686–691.

    Article  PubMed  CAS  Google Scholar 

  100. Connolly, A. J., Suh, D. Y., Hunt, T. K., and Coughlin, S. R. (1997) Mice lacking the thrombin receptor, PAR1, have normal skin wound healing. Am. J. Pathol. 151, 1199–1204.

    PubMed  CAS  Google Scholar 

  101. Romer, J., Bugge, T. H., Pyke C., Lund, L. R., Flick, M. J., Degen, J. L., and Dano, K. (1996) Impaired wound healing in mice with a disrupted plasminogen gene. Nat. Med. 2, 287–292.

    Article  PubMed  CAS  Google Scholar 

  102. Subramaniam, M., Saffarpour, S., Van-de-Water, L., Frenette, P. S., Mayadas, T. N., Hynes, R. O., and Wagner, D. D. (1997) Role of endothelial selectins in wound repair. Am. J. Pathol. 150, 1701–1709.

    PubMed  CAS  Google Scholar 

  103. Andersen, B., Weinberg, W. C., Rennekampff, O., et al. (1997) Functions of the POU domain genes Sknla/i and Tst-1/Oct-6/SCIP in epidermal differentiation. Genes Dev. 11, 1873–1884.

    Article  PubMed  CAS  Google Scholar 

  104. Ashcroft, G. S., Lei, K., Jin, W., Longenecker, G., Kulkarni, A. B., Greenwell-Wild, T., Hale-Donze, H., McGrady, G., Song, X. Y., and Wahl, S. M. (2000) Secretory leukocyte protease inhibitor mediates nonredundant functions necessary for normal wound healing. Nat. Med. 6, 1147–1153.

    Article  PubMed  CAS  Google Scholar 

  105. Echtermeyer, F., Streit, M., Wilcox-Adelman, S., Saoncella, S., Denhez, F., Detmar, M., and Goetinck, P. F. (2001) Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4. J. Clin. Invest. 107, R9-R14.

    Article  PubMed  CAS  Google Scholar 

  106. Forsberg, E., Hirsch, E., Frohlich, L., Meyer, M., Ekblom, P., Aszodi, A., Werner, S., and Fassler, R. (1996) Skin wounds and severed nerves heal normally in mice lacking tenascin-C. Proc. Natl. Acad. Sci. USA 93, 6594–6599.

    Article  PubMed  CAS  Google Scholar 

  107. Peterson, J. J., Rayburn, H. B., Lager, D. J., Raife, T. J., Kealey, G. P., Rosenberg, R. D., and Lentz, S. R.4.4 CXCR2 Null Mice Show Multiple Defects in Wound Healing

  108. Raife, T. J, Lager, D. J., Peterson, J. J., Erger, R. A., and Lentz, S. R. (1998) Keratinocyte-specific expression of human thrombomodulin in transgenic mice: effects on epidermal differentiation and cutaneous wound healing. J. Invest. Med. 46, 127–133.

    CAS  Google Scholar 

  109. Streit, M., Velasco, P., Riccardi, L., Spencer, L., Brown, L.F., Janes, L., Lange-Asschenfeldt, B., Yano, K., Hawighorst, T., Iruela-Arispe, L., and Detmar, M. (2000) Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice. EMBO J. 19, 3272–3282.

    Article  PubMed  CAS  Google Scholar 

  110. Kyriakides, T. R., Tam, J. W., and Bornstein, P. (1999) Accelerated wound healing in mice with a disruption of the thrombospondin 2 gene. J. Invest. Dermatol. 113, 782–787.

    Article  PubMed  CAS  Google Scholar 

  111. Carmeliet, P., Schoonjans, L., Kieckens, L., Ream, B., Degen, J., Bronson, R., De Vos, R., van den Oord, J. J., Collen, D., and Mulligan, R. C. (1994) Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368, 419–424.

    Article  PubMed  CAS  Google Scholar 

  112. Bugge, T. H., Flick, M. J., Danton, M. J., Daugherty, C. C., Romer, J., Dano, K., Carmeliet, P., Collen, D., and Degen, J. L. (1996) Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator.. Proc. Natl. Acad. Sci. USA 93, 5899–5904.

    Article  PubMed  CAS  Google Scholar 

  113. Inada, R., Matsuki, M., Yamada, K., Morishima, Y., Shen, S., Kuramoto, N., Yasuno, H., Takahashi, K., Miyachi, Y., and Yamanishi, K. (2000) Facilitated wound healing by activation of the transglutaminase 1 gene. Am. J. Pathol. 157, 1875–1882.

    PubMed  CAS  Google Scholar 

  114. Jang, Y. C., Tsou, R., Gibran, N. S., and Isik, F. F. (2000) Vitronectin deficiency is associated with increased wound fibrinolysis and decreased microvascular angiogenesis in mice. Surgery 127, 696–704.

    Article  PubMed  CAS  Google Scholar 

  115. Rodrguez-Puebla, M.L., de Marval, P.L., LaCava, M., Moons, D.S., Kiyokawa, H., Conti, C.J. (2002). Cdk4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation. Am J Pathol. 161, 405–411.

    Google Scholar 

  116. Kretz, M., Euwens, C., Hombach, S., et al. (2003). Altered connexin expression and wound healing in the epidermis of connexin-deficient mice. J Cell Sci. 116, 3443–3552.

    Article  PubMed  CAS  Google Scholar 

  117. Chen, C.C., Mo, F.E., Lau, L.F. (2001). The angiogenic factor Cyr61 activates a genetic program for wound healing in human skin fibroblasts. J Biol Chem. 276, 47329–37.

    Article  PubMed  CAS  Google Scholar 

  118. D’Souza, S.J., Vespa, A., Murkherjee, S., Maher, A., Pajak, A., Dagnino, L. (2002). E2F-1 is essential for normal epidermal wound repair. J Biol Chem. 277, 10626–10632.

    Article  PubMed  CAS  Google Scholar 

  119. Miller, D.L., Ortega, S., Bashayan, O., Basch, R., Basilico, C. (2000). Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol Cell Biol. 20, 2260–2268.

    Article  PubMed  CAS  Google Scholar 

  120. Drew, A.F., Liu, H., Davidson, J.M., Daugherty, C.C., Degen, J.L. (2001). Wound-healing defects in mice lacking fibrinogen. Blood. 97, 3691–3698.

    Article  PubMed  CAS  Google Scholar 

  121. Sakai, T., Johnson, K.J., Murozono, M., et al. (2001). Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis. Nat Med. 7, 324–330.

    Article  PubMed  CAS  Google Scholar 

  122. Muro, A.F., Chauhan, A.K., Gajovic, S., Iaconcig, A., Porro, F., Stanta, G., Baralle, F.E. (2003). Regulated splicing of the fibronectin EDA exon is essential for proper skin wound healing and normal lifespan. J Cell Biol. 162, 149–160.

    Article  PubMed  CAS  Google Scholar 

  123. Wankell, M., Munz, B., Hubner, G., Hans, W., Wolf, E., Goppelt, A., Werner, S. (2001). Impaired wound healing in transgenic mice overexpressing the activin antagonist follistatin in the epidermis. EMBO J. 20, 5361–5372.

    Article  PubMed  CAS  Google Scholar 

  124. Grose, R., Werner, S., Reichardt, H., et al. (2002). A role for endogenous glucocorticoids in wound repair. EMBO Reports. 3, 575–582.

    Article  PubMed  CAS  Google Scholar 

  125. Mann, A., Breuhahn, K., Schirmacher, P., Blessing, M. (2001). Keratinocyte-derived Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) accelerates wound healing: Stimulation of keratinocyte proliferation, granulation tissue formation, and vascularization. J Invest Dermatol. 117, 1382–1390.

    Article  PubMed  CAS  Google Scholar 

  126. Toyoda, M., Takayama, H., Horiguchi, N., et al. (2001). Overexpression of hepatocyte growth factor/scatter factor promotes vascularization and granulation tissue formation in vivo. FEBS Lett. 509, 95–100.

    Article  PubMed  CAS  Google Scholar 

  127. Mack, J.A., Abramson, S.R., Ben, Y., et al. (2003). Hoxb13 knockout adult skin exhibits high levels of hyaluronan and enhanced wound healing. FASEB J. 17, 1352–1354.

    PubMed  CAS  Google Scholar 

  128. Chen, J., Diacovo, T.G., Grenache, D.G., Santoro, S.A., Zutter, M.M. (2002). The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol. 161, 337–344.

    PubMed  CAS  Google Scholar 

  129. Grose, R., Hutter, C., Bloch, W., et al. (2002). A crucial role of 1 integrins for keratinocyte migration in vitro and during cutaneous wound repair. Development. 129, 2303–2315.

    PubMed  CAS  Google Scholar 

  130. Lin, Z.Q., Kondo, T., Ishida, Y., Takayasu, T., Mukaida, N. (2003). Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice. J Leukoc Biol. 73, 713–721.

    Article  PubMed  CAS  Google Scholar 

  131. Li, G., Gustafson-Brown, C., Hanks, S.K., et al. (2003). c-Jun is essential for organization of the epidermal leading edge. Dev Cell. 4, 865–877.

    Article  PubMed  CAS  Google Scholar 

  132. Zenz, R., Scheuch, H., Martin, P., et al. (2003). c-Jun regulates eyelid closure and skin tumor development through EGFR signaling. Dev Cell. 4, 879–889.

    Article  PubMed  CAS  Google Scholar 

  133. Grose, R., Harris, B.S., Cooper, L., Topilko, P., Martin, P. (2002). The immediate early genes krox-24 and krox-20 are rapidly upregulated following wounding in the embryonic and adult mouse. Dev Dyn. 223, 371–378.

    Article  PubMed  CAS  Google Scholar 

  134. Low, Q.E., Drugea, I.A., Duffner, L.A., et al. (2001). Wound healing in MIP-lalpha(−/−) and MCP-1(−/−) mice. Am J Pathol. 159, 457–463.

    PubMed  CAS  Google Scholar 

  135. Mohan, R., Chintala, S.K., Jung, J.C., et al. (2002). Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration. J Biol Chem. 277, 2065–2072.

    Article  PubMed  CAS  Google Scholar 

  136. Frye, M., Gardner, C., Li, E.R., Arnold, I., Watt, F.M. (2003). Evidence that Myc activation depletes the epidermal stem cell compartment by modulating adhesive interactions with the local microenvironment. Development. 130, 2793–2808.

    Article  PubMed  CAS  Google Scholar 

  137. Most, D., Efron, D.T., Shi, H.P., Tantry, U.S., Barbul, A. (2002). Characterization of incisional wound healing in inducible nitric oxide synthase knockout mice. Surgery. 132, 866–876.

    Article  PubMed  Google Scholar 

  138. Ekstrand, A.J., Cao, R., Bjorndahl, M., et al. (2003). Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing. Proc Natl Acad Sci USA. 100, 6033–6038.

    Article  PubMed  CAS  Google Scholar 

  139. Braun, S., Hanselmann, C., Gassmann, M.G., et al. (2002). Nrf2 Transcription Factor, a Novel Target of Keratinocyte Growth Factor Action Which Regulates Gene Expression and Inflammation in the Healing Skin Wound. Mol Cell Biol. 22, 5492–5505.

    Article  PubMed  CAS  Google Scholar 

  140. Chan, J.C., Duszczyszyn, D.A., Castellino, F.J., Ploplis, V.A. (2001). Accelerated skin wound healing in plasminogen activator inhibitor-1-deficient mice. Am J Pathol. 159, 1681–1688.

    PubMed  CAS  Google Scholar 

  141. Chuang-Tsai, S., Sisson, T.H., Hattori, N., et al. (2003). Reduction in fibrotic tissue formation in mice genetically deficient in plasminogen activator inhibitor-1. Am J Pathol. 163, 445–452.

    PubMed  CAS  Google Scholar 

  142. Buetow, B.S., Crosby, J.R., Kaminski, W.E., et al. (2001). Platelet-derived growth factor B-chain of hematopoietic origin is not necessary for granulation tissue formation and its absence enhances vascularization. Am J Pathol. 159, 1869–1876.

    PubMed  CAS  Google Scholar 

  143. Chida, K., Hara, T., Hirai, T., et al. (2003). Disruption of protein kinase C eta results in impairment of wound healing and enhancement of tumor formation in mouse skin carcinogenesis. Cancer Res. 63, 2404–2408.

    PubMed  CAS  Google Scholar 

  144. Carmeliet, P., Moons, L., Luttun, A., et al. (2001). Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med. 5:575–583.

    Article  CAS  Google Scholar 

  145. Michalik, L., Desvergne, B., Tan, N.S., et al. (2001). Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice. J Cell Biol. 154, 799–814.

    Article  PubMed  CAS  Google Scholar 

  146. Tan, N.S., Michalik, L., Noy, N., et al. (2001). Critical roles of PPAR beta/delta in keratinocyte response to inflammation. Genes and Dev. 15, 3263–3277.

    Article  PubMed  CAS  Google Scholar 

  147. Martin, P., D’Souza, D., Martin, J., et al. (2003). Wound healing in the PU.1 null mouse-tissue repair is not dependent on inflammatory cells. Curr Biol. 13, 1122–1128.

    Article  PubMed  CAS  Google Scholar 

  148. Flanders, K.C., Sullivan, C.D., Fujii, M., et al. (2002). Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol. 160, 1057–1068.

    PubMed  CAS  Google Scholar 

  149. Stepp, M.A., Gibson, H.E., Gala, P.H., Iet asl. (2002). Defects in keratinocyte activation during wound healing in the syndecan-1-deficient mouse. J Cell Sci. 115, 4517–4531.

    Article  PubMed  CAS  Google Scholar 

  150. Cao, T., Grant, A.D., Gerard, N.P., Brain, S.D. (2001). Lack of a significant effect of deletion of the tachykinin neurokinin-1 receptor on wound healing in mouse skin. Neuroscience. 108, 695–700.

    Article  PubMed  CAS  Google Scholar 

  151. Jameson, J., Ugarte, K., Chen, N., et al. (2002). A Role for Skin gamma delta T Cells in Wound Repair. Science. 296, 747–749.

    Article  PubMed  CAS  Google Scholar 

  152. Gonzalez-Suarez, E., Samper, E., Ramirez, A., et al.. (2001). Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 20, 2619–2630.

    Article  PubMed  CAS  Google Scholar 

  153. Luetteke, N.C., Qiu, T.H., Peiffer, R.L., Oliver, P., Smithies, O., Lee, D.C. (1993). TGF alpha deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice. Cell. 73, 263–278.

    Article  PubMed  CAS  Google Scholar 

  154. Mann, G.B., Fowler, K.J., Gabriel, A., Nice, E.C., Williams, R.L., Dunn, A.R. (1993). Mice with a null mutation of the TGF alpha gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation. Cell. 73, 249–261.

    Article  PubMed  CAS  Google Scholar 

  155. Kim, I., Mogford, J.E., Chao, J.D., Mustoe, T.A. (2001). Wound epithelialization deficits in the transforming growth factor-alpha knockout mouse. Wound Repair Regen. 9, 386–390.

    Article  PubMed  CAS  Google Scholar 

  156. Koch, R.M., Roche, N.S., Parks, W.T., Ashcroft, G.S., Letterio, J.J., Roberts, A.B. (2000). Incisional wound healing in transforming growth factor-beta1 null mice. Wound Repair Regen. 8, 179–191.

    Article  PubMed  CAS  Google Scholar 

  157. Yang, L., Chan, T., Demare, J., Iwashina, T., Ghahary, A., Scott, P.G., Tredget, E.E. (2001). Healing of burn wounds in transgenic mice overexpressing transforming growth factor-beta 1 in the epidermis. Am J Pathol. 159, 2147–2157.

    PubMed  CAS  Google Scholar 

  158. Chan, T., Ghahary, A., Demare, J., Yang, L., Iwashina, T., Scott, P., Tredget, E.E. (2002). Development, characterization, and wound healing of the keratin 14 promoted transforming growth factor-beta1 transgenic mouse. Wound Repair Regen. 10, 177–187.

    Article  PubMed  Google Scholar 

  159. Amendt, C., Mann, A., Schirmacher, P., Blessing, M. (2002). Resistance of keratinocytes to TGFbeta-mediated growth restriction and apoptosis induction accelerates re-epithelialization in skin wounds. J Cell Sci. 115, 2189–2198.

    PubMed  CAS  Google Scholar 

  160. Mori, R., Kondo, T., Ohshima, T., Ishida, Y., Mukaida, N. (2002). Accelerated wound healing in tumor necrosis factor receptor p55-deficient mice with reduced leukocyte infiltration. FASEB J. 16, 963–974.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard Grose.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grose, R., Werner, S. Wound-healing studies in transgenic and knockout mice. Mol Biotechnol 28, 147–166 (2004). https://doi.org/10.1385/MB:28:2:147

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/MB:28:2:147

Index Entries

Navigation