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.
Similar content being viewed by others
References
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.
Ornitz, D. M. and Itoph, N. (2001) Fibroblast growth factors. Genome Biol. 2, 3005.1–3005.12.
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.
Johnson, D. E. and Williams, L. T. (1993) Structural and functional diversity in the FGF receptor multigene family. Adv. Cancer Res. 60, 1–41.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Sibilia, M. and Wagner, E. F. (1995) Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–238.
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.
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.
Bikfalvi, A., Klein, S., Pintucci, G., and Rifkin, D. B. (1997) Biological roles of fibroblast growth factor-2. Endocr. Rev. 18, 26–45.
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.
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.
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.
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.
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.
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.
Massagué, J. (1990) The transforming growth factor-b family. Annu. Rev. Cell Biol. 6, 597–641.
Massague, J. and Wotton, D. (2000) Transcriptional control by the TGF-beta/Smad signaling system. EMBO J. 19, 1745–1754.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Greenhalgh, D. G. and Gamelli, R. L. (1987) Is impaired wound healing caused by infection or nutritional depletion? Surgery 102, 306–312.
Reed, B. R. and Clark, R. A. (1985) Cutaneous tissue repair: practical implications of current knowledge. II. J. Am. Acad. Dermatol. 13, 919–941.
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.
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.
Massague, J. (1998) TGF-β signal transduction. Annu. Rev. Biochem. 67, 753–791.
Derynck, R., Zhang, Y., and Feng, X. H. (1998) Smads: transcriptional activators of TGF-β responses. Cell 95, 737–740.
Ashcroft, G. S. and Roberts, A. B. (2000) Loss of Smad3 modulates wound healing. Cytokine Growth Factor Rev. 11, 125–131.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Paquet, P. and Pierard, G. E. (1996) Interleukin-6 and the skin. Int. Arch. Allergy Immunol. 109, 308–317.
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.
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.
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.
Bromberg, J. (2001) Activation of STAT proteins and growth control. Bioessays 23, 161–169.
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.
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.
Devalaraja, M. N. and Richmond, A. (1999) Multiple chemotactic factors: fine control or redundancy? Trends Pharmacol. Sci. 20, 151–156.
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.
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.
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.
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.
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.
Martin, P. (1997) Wound healing-aiming for perfect skin regeneration. Science 276, 75–81.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Grose, R., Werner, S., Reichardt, H., et al. (2002). A role for endogenous glucocorticoids in wound repair. EMBO Reports. 3, 575–582.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Jameson, J., Ugarte, K., Chen, N., et al. (2002). A Role for Skin gamma delta T Cells in Wound Repair. Science. 296, 747–749.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Rights 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
Issue Date:
DOI: https://doi.org/10.1385/MB:28:2:147