Wound Healing in Mammals and Amphibians: Toward Limb Regeneration in Mammals

  • Aiko Kawasumi
  • Natsume Sagawa
  • Shinichi Hayashi
  • Hitoshi Yokoyama
  • Koji TamuraEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 367)


Mammalian fetal skin regenerates perfectly, but adult skin repairs by the formation of scar tissue. The cause of this imperfect repair by adult skin is not understood. In contrast, wounded adult amphibian (urodeles and anurans) skin is like mammalian fetal skin in that it repairs by regeneration, not scarring. Scar-free wound repair in adult Xenopus is associated with expression of the paired homeobox transcription factor Prx1 by mesenchymal cells of the wound, a feature shared by mesenchymal cells of the regeneration blastema of the axolotl limb. Furthermore, mesenchymal cells of Xenopus skin wounds that harbor the mouse Prx1-limb-enhancer as a transgene exhibit activation of the enhancer despite the fact that they are Xenopus cells, suggesting that the mouse Prx1 enhancer possesses all elements required for its activation in skin wound healing, even though activation of the same enhancer in the mouse is not seen in the wounded skin of an adult mouse. Elucidation of the role of the Prx1 gene in amphibian skin wound healing will help to clarify the molecular mechanisms of scarless wound healing. Shifting the molecular mechanism of wound repair in mammals to that of amphibians, including reactivation of the Prx1-limb-enhancer, will be an important clue to stimulate scarless wound repair in mammalian adult skin. Finding or creating Prx1-positive stem cells in adult mammal skin by activating the Prx1-limb-enhancer may be a fast and reliable way to provide for scarless skin wound repair, and even directly lead to limb regeneration in mammals.


Wound Healing Limb Regeneration Fetal Fibroblast Adult Skin Blastema Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Apical epithelial cap






Extracellular matrix


Endothelial progenitor cell




Migration inhibitory factor


Matrix metalloproteinase


Platelet-derived growth factor


Transforming growth factor


Vascular endothelial growth factor


  1. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN (2001) Peripheral blood fibrocytes: differntiation pathway and migration to wound sites. J Immunol 166:7556–7562PubMedGoogle Scholar
  2. Bellingan GJ, Caldwell H, Howie SE, Dransfield I, Haslett C (1996) 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 157:2577–2585PubMedGoogle Scholar
  3. Bodemer CW (1959) Observations on the mechanism of induction of supernumerary limbs in adult Triturus viridescens. J Exp Zool 140:79–99PubMedCrossRefGoogle Scholar
  4. Carlson MR, Bryant SV, Gardiner DM (1998) Expression of Msx-2 during development, regeneration, and wound healing in axolotl limbs. J Exp Zool 282:715–723PubMedCrossRefGoogle Scholar
  5. Cass DL, Sylvester KG, Yang EY, Crombleholme TM, Adzick NS (1997) Myofibroblast persistence in fetal sheep wounds is associated with scar formation. J Pediatr Surg 32:1017–1021PubMedCrossRefGoogle Scholar
  6. Cass DL, Bullard KM, Sylvester KG, Yang EY, Sheppard D, Herlyn M, Adzick NS (1998) Epidermal integrin expression is upregulated rapidly in human fetal wound repair. J Pediatr Surg 33:312–316PubMedCrossRefGoogle Scholar
  7. Ceradini DJ, Kulkami AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864PubMedCrossRefGoogle Scholar
  8. Chen WY, Grant ME, Schor AM, Schor SL (1989) Differences between adult and foetal fibroblasts in the regulation of hyaluronate synthesis: correlation with migratory activity. J Cell Sci 94:577–584PubMedGoogle Scholar
  9. Clark RAF (1996) The molecular and cellular biology of wound repair, 2nd edn. Plenum Press, New York, pp 427–474Google Scholar
  10. Cowin AJ, Brosnan MP, Holmes TM, Ferguson MW (1998) Endogenous inflammatory response to dermal wound healing in the fetal and adult mouse. Dev Dyn 212:385–393PubMedCrossRefGoogle Scholar
  11. Cowin AJ, Holmes TM, Brosnan P, Ferguson MW (2001) Expression of TGF-beta and its receptors in murine fetal and adult dermal wounds. Eur J Dermatol 11:424–431PubMedGoogle Scholar
  12. Dent JN (1962) Limb regeneration in larvae and metamorphosing individuals of the South African clawed toad. J Morphol 110:61–77PubMedCrossRefGoogle Scholar
  13. Ellis IR, Schor SL (1996) Differential effects of TGF-beta1 on hyaluronan synthesis by fetal and adult skin fibroblasts: implications for cell migration and wound healing. Exp Cell Res 228:326–333PubMedCrossRefGoogle Scholar
  14. Endo T, Bryant SV, Gardiner DM (2004) A stepwise model system for limb regeneration. Dev Biol 270:135–145PubMedCrossRefGoogle Scholar
  15. Enoch S, Grey JE, Harding KG (2006) Recent advances and emerging treatments. Br Med J 332:962–965CrossRefGoogle Scholar
  16. Ferguson MW, O’Kane S (2004) Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Philos Trans R Soc Lond B Biol Sci 359:839–850PubMedCrossRefGoogle Scholar
  17. Gordillo GM, Sen CK (2003) Revisiting the essential role of oxygen in wound healing. Am J Surg 186:259–263PubMedCrossRefGoogle Scholar
  18. Grieb G, Piatkowski A, Simons D, Hormann N, Dewor M, Steffans G, Bernhagen J, Pallua N (2010) Macrophage migration inhibitory factor is a potential inducer of endothelial progenitor cell mobilization after flap operation. Surgery 151:268–277PubMedCrossRefGoogle Scholar
  19. Hopkinson-Woolley J, Hughes D, Gordon S, Martin P (1994) Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse. J Cell Sci 107:1159–1167PubMedGoogle Scholar
  20. Levenson SM, Geever EF, Vrowley LV, Oates JF 3rd, Berard CW, Rosen H (1965) The healing of rat skin wounds. Ann Surg 161:293–308PubMedCrossRefGoogle Scholar
  21. Lévesque M, Villiard E, Roy S (2010) Skin wound healing in axolotls: a scarless process. J Exp Zool B Mol Dev Evol 314:684–697PubMedCrossRefGoogle Scholar
  22. Lheureux E (1977) Importance of limb tissue associations in the development of nerve-induced supernumerary limbs in the newt Pleurodeles waltlii Michah. J Embryol Exp Morphol 38:151–173PubMedGoogle Scholar
  23. Lorenz HP, Adzick NS (1993) Scarless skin wound repair in the fetus. West J Med 159:350–355PubMedGoogle Scholar
  24. Malcolm M, Holder N (1984) Axial characteristics of nerve induced supernumerary limbs in the axolotl. Roux’s Arch.\ Dev Biol 193:394–401Google Scholar
  25. Martin P, Lewis J (1992) Actin cables and epidermal movement in embryonic wound healing. Nature 360:179–183PubMedCrossRefGoogle Scholar
  26. Martin P, Dickson MC, Millan FA, Akhurst RJ (1993) Rapid induction and clearance of TGF beta 1 is an early response to wounding in the mouse embryo. Dev Genet 14:225–238PubMedCrossRefGoogle Scholar
  27. Martin P, D’Souza D, Martin J, Grose R, Cooper L, Maki R, McKercher SR (2003) Wound healing in the PU.1 null mouse–tissue repair is not dependent on inflammatory cells. Curr Biol 13:1122–1128PubMedCrossRefGoogle Scholar
  28. Mast BA (1992) The skin. In: Cohen IK, Diegelmann RF, Lindblad WJ (eds) Wound Healing: Biochemical and Clinical Aspects. WB Saunders, Philadelphia, pp 344–355Google Scholar
  29. Matoltsy AG, Downes AM, Sweeney TM (1968) Studies of the epidermal water barrier. II investigation of the chemical nature of the water barrier. J Invest Dermatol 50:19–26PubMedGoogle Scholar
  30. McKean DM, Sisbarro L, Ilic D, Kaplan-Alburquerque N, Nemenoff R, Weiser-Evans M, Kern MJ, Jones PL (2003) FAK induces expression of Prx1 to promote tenascin-C-dependent fibroblast migration. J Cell Biol 161:393–402PubMedCrossRefGoogle Scholar
  31. Mukouyama YS, Shin D, Britsch S, Taniguchi M, Anderson DJ (2002) Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin. Cell 109:693–705PubMedCrossRefGoogle Scholar
  32. Muneoka K, Holler-Dinsmore G, Bryant SV (1986) Intrinsic control of regenerative loss in Xenopus laevis limbs. J Exp Zool 240:47–54PubMedCrossRefGoogle Scholar
  33. Muneoka K, Sassoon D (1992) Molecular aspects of regeneration in developing vertebrate limbs. Dev Biol 152:37–49PubMedCrossRefGoogle Scholar
  34. Nickoloff BJ, Mitra RS, Riser BL, Dixit VM, Varani J (1988) Modulation of keratinocyte motility. Correlation with production of extracellular matrix molecules in response to growth promoting and antiproliferative factors. Am J Pathol 132:543–551PubMedGoogle Scholar
  35. Oztürk S, Deveci M, Sengezer M, Günhan O (2001) Results of artificial inflammation in scarless foetal wound healing: an experimental study in foetal lambs. Br J Plast Surg 54:47–52PubMedCrossRefGoogle Scholar
  36. Poll CP (2009) Wound Management in Amphibians: etiology and Treatment of Cutaneous Lesions. J Exotic Pet Med 18:20–35CrossRefGoogle Scholar
  37. Putnins EE, Firth JD, Lohachitranont A, Uitto VJ, Larjava H (1999) Keratinocyte growth factor (KGF) promotes keratinocyte cell attachment and migration on collagen and fibronectin. Cell Adhes Commun 7:211–221PubMedCrossRefGoogle Scholar
  38. Repesh LA, Oberpriller JC (1978) Scanning electron microscopy of epidermal cell migration in wound healing during limb regeneration in the adult newt, Notophthalmus viridescens. Am J Anat 151:539–555PubMedCrossRefGoogle Scholar
  39. Reynolds S, Holder N, Fernandes M (1983) The form and structure of supernumerary hindlimbs formed following skin grafting and nerve deviation in the newt Triturus cristatus. J Embryol Exp Morphol 77:221–241PubMedGoogle Scholar
  40. Satoh A, Gardiner DM, Bryant SV, Endo T (2007) Nerve-induced ectopic limb blastemas in the axolotl are equivalent to amputation-induced blastemas. Dev Biol 312:231–244PubMedCrossRefGoogle Scholar
  41. Seifert AW, Monaghan JR, Voss SR, Maden M (2012) Skin regeneration in adult axolotls: a blueprint for scar-free healing in vertebrates. PLoS ONE 7(4):e32875PubMedCrossRefGoogle Scholar
  42. Sessions SK, Bryant SV (1988) Evidence that regenerative ability is an intrinsic property of limb cells in Xenopus. J Exp Zool 247:39–44PubMedCrossRefGoogle Scholar
  43. Shah M, Foreman DM, Ferguson MW (1994) Neutralising antibody to TGF-beta 1,2 reduces cutaneous scarring in adult rodents. J Cell Sci 107:1137–1157PubMedGoogle Scholar
  44. Shah M, Foreman DM, Ferguson MW (1995) 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 108:985–1002PubMedGoogle Scholar
  45. Soo C, Beanes SR, Hu FY, Zhang X, Dang C, Chang G, Wang Y, Nishimura I, Freymiller E, Longaker MT, Lorenz HP, Ting K (2003) Ontogenetic transition in fetal wound transforming growth factor-beta regulation correlates with collagen organization. Am J Pathol 163:2459–2476PubMedCrossRefGoogle Scholar
  46. Stocum DL (2011) The role of peripheral nerves in urodele limb regeneration. Eur J Neurosci 34:908–916PubMedCrossRefGoogle Scholar
  47. Suzuki M, Satoh A, Ide H, Tamura K (2005) Nerve-dependent and -independent events in blastema formation during Xenopus froglet limb regeneration. Dev Biol 286:361–375PubMedCrossRefGoogle Scholar
  48. Suzuki M, Yakushiji N, Nakada Y, Satoh A, Ide H, Tamura K (2006) Limb regeneration in Xenopus laevis froglet. Sci World J 6:26–37CrossRefGoogle Scholar
  49. Suzuki M, Satoh A, Ide H, Tamura K (2007) Transgenic Xenopus with prx1 limb enhancer reveals crucial contribution of MEK/ERK and PI3 K/AKT pathways in blastema formation during limb regeneration. Dev Biol 304:675–686PubMedCrossRefGoogle Scholar
  50. Tamura K, Ohgo S, Yokoyama H (2010) Limb blastema cell: a stem cell for morphological regeneration. Dev Growth Differ 52:89–99PubMedCrossRefGoogle Scholar
  51. Tepper OM, Capla JM, Galiano RD, Ceradini DJ, Callaghan MJ, Kleinman ME, Gurtner GC (2005) Adult vasculogenesis occurs through in situ recruitment, proliferatioon, and tubulization of circulating bone marrow-derived cells. Blood 105:1068–1077PubMedCrossRefGoogle Scholar
  52. Ulrich D, Lichtenegger F, Unglaub F, Smeets R, Pallua N (2005) Effect of chronic wound exudates and MMP-2/-9 inhibitor on angiogenesis in vitro. Plast Reconstr Surg 116:539–545PubMedCrossRefGoogle Scholar
  53. Velazquez OC (2007) Angiogenesis and vasculogenesis: inducing the growth of new blood vessels and wound healing by stimulation of bone marrow-derived progenitor cell mobilization and homing. J Vasc Surg 45:A39–A47PubMedCrossRefGoogle Scholar
  54. Werner S, Richard G (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83:835–870PubMedGoogle Scholar
  55. Whitby DJ, Ferguson MW (1991) The extracellular matrix of lip wounds in fetal, neonatal and adult mice. Development 122:651–668Google Scholar
  56. Whitby DJ, Longaker MT, Harrison MR, Adzick NS, Ferguson MW (1991) Rapid epithelialisation of fetal wounds is associated with the early deposition of tenascin. J Cell Sci 99:583–586PubMedGoogle Scholar
  57. Wong VW, Sorkin M, Glotzbach JP, Longaker MT, Gurtner GC (2011) Surgical approaches to create murine models of human wound healing. J Biomed Biotechnol 969618. Epub 1 Dec 2010Google Scholar
  58. Wu L, Siddiqui A, Morris DE, Cox DA, Roth SI, Mustoe TA (1977) Transforming growth factor beta 3 (TGF beta 3) accelerates wound healing without alteration of scar prominence. Histologic and competitive reverse-transcription-polymerase chain reaction studies. Arch Surg 132:753–760CrossRefGoogle Scholar
  59. Wulff BC, Parent AE, Meleski MA, DiPietro LA, Schrementi ME, Wilgus TA (2012) Mast cells contribute to scar formation during fetal wound healing. J Invest Dermatol 132:458–465PubMedCrossRefGoogle Scholar
  60. Yang EV, Bryant SV (1994) Developmental regulation of a matrix metalloproteinase during regeneration of axolotl appendages. Dev Biol 166:696–703PubMedCrossRefGoogle Scholar
  61. Yakushiji N, Yokoyama H, Tamura K (2009) Repatterning in amphibian limb regeneration: a model for study of genetic and epigenetic control of organ regeneration. Semin Cell Dev Biol 20:565–574PubMedCrossRefGoogle Scholar
  62. Yokoyama H, Maruoka T, Aruga A, Amano T, Ohgo S, Shiroishi T, Tamura K (2011) Prx-1 expression in Xenopus laevis scarless skin-wound healing and its resemblance to epimorphic regeneration. J Invest Dermatol 131:2477–2485PubMedCrossRefGoogle Scholar
  63. Yoshizato K (2007) Molecular mechanism and evolutional significance of epithelial-mesenchymal interactions in the body- and tail-dependent metamorphic transformation of anuran larval skin. Int Rev Cytol 260:213–260PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Aiko Kawasumi
    • 1
  • Natsume Sagawa
    • 1
  • Shinichi Hayashi
    • 1
  • Hitoshi Yokoyama
    • 1
  • Koji Tamura
    • 1
    Email author
  1. 1.Department of Developmental Biology and Neurosciences, Graduate School of Life SciencesTohoku UniversitySendaiJapan

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