Reepithelialisation of Wounds

  • I. M. Leigh


Reepithelialisation of wounds involves a number of different processes affecting the biology of the keratinocyte. Following breaching of the epidermis the keratinocytes must first migrate across the surface of the denuded area, then mitosis must occur close to the edge to expand the population (Odland and Ross 1968; Krawczyck 1971; Clark 1985). Once keratinocytes have covered the defect they must establish a basement membrane zone, which aids keratinocyte attachment. Then stratification and differentiation must occur to normalise the newly regenerated epidermis. Subsequently the dermis is remodelled, which also involves the keratinocytes by keratinocytemesenchymal interactions mediated by cell contact, diffusible cytokines and extracellular matrix proteins. Replacement of a denuded area of skin by different forms of skin grafts, including keratinocyte sheets, will accelerate the epithelialisation process. These biological processes of keratinocytes will be discussed following an introduction to keratinocyte culture, which provides the basis for many observations applicable to wound healing.


Wound Healing Bullous Pemphigoid Human Epidermal Keratinocytes Venous Ulcer Skin Equivalent 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams JC, Watt FM (1989) Fibronectin inhibits the terminal differentiation of human keratinocytes. Nature 340:307–309.PubMedCrossRefGoogle Scholar
  2. Adams JC, Watt FM (1990) Changes in keratinocyte adhesion during terminal differentiation: reduction in fibronectin binding precedes α5β1 integrin loss from cell surface. J Cell Biol 110:1387–1404.CrossRefGoogle Scholar
  3. Adams JC, Watt FM (1991) Expression of β1,β3,β4,β5 integrins by human epidermal keratinocytes and nondifferentiating keratinocytes. J Cell Biol 115:829–841.PubMedCrossRefGoogle Scholar
  4. Albers KM, Setzer RW, Taichman L (1986) Heterogeneity in the replicating population of cultured human epidermal keratinocytes. Differentiation 31:134–140.PubMedCrossRefGoogle Scholar
  5. Alitalo K, Kuismanen E, Myllyla R, Kiistala U, Asko-Selijavaara S, Vaheri A (1982) Extracellular proteins of human epidermal keratinocytes and feeder 3T3 cells. J Cell Biol 94:497–505.PubMedCrossRefGoogle Scholar
  6. Asselinean D, Pruneiras M (1984) Reconstruction of “simplified” skin: control of fabrication. Br J Dermatol 111 Suppl 27:219–222.CrossRefGoogle Scholar
  7. Barker JNWN, Sarma V, Mitra RS, Dixit V, Nickoloff BJ (1990) Marked synergism between tumour necrosis factor α and interferon gamma in the regulation of keratinocyte derived adhesion molecules and chemotactic factors. J Clin Invest 85:605–608.PubMedCrossRefGoogle Scholar
  8. Barrandon Y, Green H (1987) Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-α and epidermal growth factor. Cell 50:1131–1137.PubMedCrossRefGoogle Scholar
  9. Bell E, Sher S, Hull B, Merrill C, Rosen S, Chamson A, Asselineau D, Dubertret L, Coulomb B, Lapier C, Nusgens B, Nevreux Y (1983) The reconstruction of living skin. J Invest Dermatol 81:2s–10s.PubMedCrossRefGoogle Scholar
  10. Blair SD, Backhouse CM, Wright DDI, Riddle E, McCollum CN (1988a) Do dressings influence the healing of chronic venous ulcers?. Phlebology 3:129–134.Google Scholar
  11. Blair SD, Wright DDI, Backhouse CM, Riddle E, McCollum CN (1988b) Sustained compression and healing of chronic venous ulcers. Br Med J 297:1159–1161.CrossRefGoogle Scholar
  12. Boyce ST, Hansbrough JF (1988) Biologic attachment, growth, and differentiation of cultured human epidermal keratinocytes on a graftable collagen and chondroitin-6 sulfate substrate. Surgery 103:421–431.PubMedGoogle Scholar
  13. Boyce ST, Ham RG (1985) Cultivation, frozen storage, and clonal growth of normal human epidermal keratinocytes in serum-free media. J Tissue Cult Methods 9:83–93.CrossRefGoogle Scholar
  14. Brain A, Purkis P, Coates P, Hackett M, Navsaria H, Leigh IM (1989) Survival of cultured allogeneic keratinocytes transplanted to deep dermal bed assessed with probe specific for Y chromosome. Br Med J 298:917–919.CrossRefGoogle Scholar
  15. Briggaman R, Wheeler CE Jr (1975) The epidermal-dermal junction. J Invest Dermatol 65:71–84.PubMedCrossRefGoogle Scholar
  16. Burke JF, Yannas IV, Quinby WC, Bondoc CC, Jung WK (1981) Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury. Ann Surg 194:413–427.PubMedCrossRefGoogle Scholar
  17. Burt AM, Pallett CD, Sloane JP, O’Hare MJ, Schafler KF, Yardeni P, Eldad A, Clarke JA, Gusterson BA (1989) Survival of cultured allografts in burns assessed with probe specific for Y chromosome. Br Med J 298:915–917.CrossRefGoogle Scholar
  18. Carter WG, Wayner EA, Bouchard TS, Kaur P (1990) The role of integrins α2β1 and α3β1 in cell-cell and cell-substrate adhesion of human epidermal cells. J Cell Biol 110:1387–1404.PubMedCrossRefGoogle Scholar
  19. Carver N, Leigh IM (1992) Synthetic dressings. Int J Dermatol 31:10–18.PubMedCrossRefGoogle Scholar
  20. Clark RAF (1985) Cutaneous tissue repair: basic biologic considerations. J Am Acad Dermatol 13:701–725.PubMedCrossRefGoogle Scholar
  21. Clark RAF (1990) Fibronectin matrix deposition and fibronectin receptor expression in healing and normal skin. J Invest Dermatol 96:128s–134s.CrossRefGoogle Scholar
  22. Clark RAF, Lanigan JM, Delia Pelle P, Manseau E, Dvorak HF, Colvin RB (1982) Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. J Invest Dermatol 79:264–269.PubMedCrossRefGoogle Scholar
  23. Coffey RJ, Derynck R, Wilcox JN, Bringman TS, Goustin AS, Moses HL, Pittelkow MR (1987) Production and auto-induction of transforming growth factor alpha in human keratinocytes. Nature 328:817–820.PubMedCrossRefGoogle Scholar
  24. Compton CC, Gill JM, Bradford DA, Regauer S, Gallico GG, O’Connor NE (1989) Skin regenerated from cultured epithelial autografts on full thickness burns wounds from 6 days to 5 years after grafting. Lab Invest 60:600–612.PubMedGoogle Scholar
  25. Cotsarelis G, Sun T-T, Lavker RM (1990) Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61:1329–1337.PubMedCrossRefGoogle Scholar
  26. Cuono C, Langdon R, McGuire J (1986) Use of cultured epidermal autografts and dermal allografts as skin replacement after burn injury. Lancet 1:1123–1124.PubMedCrossRefGoogle Scholar
  27. Cuono C, Langdon R, Birchall N, Barttelbort S, McGuire J (1987) Composite autologousallogenic skin replacement: development and clinical application. Plast Reconstr Surg 80:626–635.PubMedCrossRefGoogle Scholar
  28. Fuchs E (1990) Epidermal differentiation. Curr Opin Cell Biol 2:1028–1035.PubMedCrossRefGoogle Scholar
  29. Green H (1978) Cyclic AMP in relation to proliferation of the epidermal cell: a new view. Cell 15:801–811.PubMedCrossRefGoogle Scholar
  30. Green H (1980) The keratinocyte as differentiated cell type. Harvey Lect Ser 74:101–139.Google Scholar
  31. Green H, Kehinde O, Thomas J (1979) Growth of cultured human epidermal cells into multiple epithelia suitable for grafting. Proc Natl Acad Sci USA 76:5665–5668.PubMedCrossRefGoogle Scholar
  32. Grinnell F (1992) Wound repair, keratinocyte activation and integrin modulation. J Cell Sci 101:1–5.PubMedGoogle Scholar
  33. Grossman RM, Krueger J, Yourish D (1989) IL6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci USA 86:6367–6371.PubMedCrossRefGoogle Scholar
  34. Guo M, Toda K-I, Grinnell F (1990) Activation of human keratinocyte migration on type I collagen and fibronectin. J Cell Sci 96:197–205.PubMedGoogle Scholar
  35. Hansborough JF, Boyce ST, Cooper ML, Foreman TJ (1989) Burn wound closure with cultured autologous keratinocytes and fibroblasts attached to a collagen-glycosaminoglycan substrate. JAMA 262:2125–2130.CrossRefGoogle Scholar
  36. Heck EL, Bergstresser PR, Baxter CR (1985) Composite skin grafts: frozen dermal allografts support the engraftment and expansion of autologous epidermis. J Trauma 25:106–112.PubMedCrossRefGoogle Scholar
  37. Hennings H, Michael D, Cheng C, Steinert P, Holbrook K, Yuspa SH (1980) Calcium regulation of growth and differentiation of mouse epidermal cells in culture. Cell 19:245–254.PubMedCrossRefGoogle Scholar
  38. Hertle M, Kubier M-D, Leigh IM, Watt FM (1992) Aberrant integrin expression during epidermal wound healing and in psoriatic epidermis. J Clin Invest 89:1892–1901.PubMedCrossRefGoogle Scholar
  39. Holbrook KA (1989) Biological structure and function: perspectives on morphological approaches to the study of the granular layer keratinocyte. J Invest Dermatol 92:84–104.CrossRefGoogle Scholar
  40. Holbrook KA, Wolff K (1987) Structure and development of skin. In: Fitzpatrick TB, Eisen AZ, Wolf K, Freidberg IM, Austen KF (eds) Dermatology in general medicine, 3rd edn. McGraw-Hill, New York, pp 93–131.Google Scholar
  41. Hull BE, Finley RK, Miller SF (1990) Coverage of full thickness burns with bilayered skin equivalents: a preliminary clinical trial. Surgery 107:496–502.PubMedGoogle Scholar
  42. Hunter JAA, McVittie E, Comaish JS (1974) Light and electron microscopy studies of physical injury to the skin. I. Suction. Br J Dermatol 90:481–490.PubMedCrossRefGoogle Scholar
  43. Hynes RO (1987) Integrins: a family of cell surface receptors. Cell 48:549–554.PubMedCrossRefGoogle Scholar
  44. Krawczyck WS (1971) A pattern of epidermal cell migration during wound healing. J Cell Biol 49:247–263.CrossRefGoogle Scholar
  45. Kupper TS, Horowitz M, Birchall N, Mizutani H, Coleman D, McGuire J, Flood P, Dower S, Lee F (1988) Haemopoietic, lymphopoietic and proinflammatory cytokines produced by human and murine keratinocytes. Ann N Y Acad Sci 548:262–270.PubMedCrossRefGoogle Scholar
  46. Leigh IM, McKay I, Carver N, Navsaria H, Green C (1991) Skin equivalents and cultured skin: from the Petri dish to the patient. Wounds 3:141–148.Google Scholar
  47. Lynch SE, Nixon JC, Colvin RB, Antoniades HN (1987) Role of platelet derived growth factor in wound healing: synergistic effects with other growth factors. Proc Natl Acad Sci USA 84:7696–7700.PubMedCrossRefGoogle Scholar
  48. Mackenzie IC, Fusenig NE (1983) Regeneration of organized epithelial structure. J Invest Dermatol 81:189s–194s.PubMedCrossRefGoogle Scholar
  49. Mackenzie IC, Hill MW (1984) Connective tissue influences on patterns of epithelial architecture and keratinisation in skin and oral mucosa of the adult mouse. Cell Tissue Res 235:551–559.PubMedCrossRefGoogle Scholar
  50. Mackenzie RC, Sauder DN (1990) Keratinocyte cytokines and growth factors. Dermatol Clin 8:649–661.Google Scholar
  51. Mansbridge JN, Knapp AM (1987) Changes in keratinocyte maturation during wound healing. J Invest Dermatol 89:253–263.PubMedCrossRefGoogle Scholar
  52. McGrath J, Scofield OMV, Ishida-Yamaoto A, O’Grady A, Mayou BJ, Navsaria H, Leigh IM, Eady RAJ (1993) Cultured keratinocyte allografts and wound healing in severe recessive dystrophic epidermolysis bullosa. J Am Acad Dermatol 29:407–419.PubMedCrossRefGoogle Scholar
  53. McKay IA, Leigh IM (1990) Epidermal cytokines and their roles in cutaneous wound healing. Br J Dermatol 124:513–518.CrossRefGoogle Scholar
  54. Moll MAE, Nanning PB, van Eendenburg J-P, Westerhof W, Mekkes JR, van Ginkel CJ (1991) Grafting of venous ulcers; an intraindividual comparison between cultured skin quivalents and full thickness skin punch grafts. J Am Acad Dermatol 2:77–82.CrossRefGoogle Scholar
  55. Mustoe TA, Pierce GF, Thomason P, Gramates P, Sporn MB, Dueul TF (1987) Accelerated healing of incisional wounds in rats induced by transforming growth factor beta. Science 237:1333–1336.PubMedCrossRefGoogle Scholar
  56. Nathan C, Sporn M (1991) Cytokines in context. J Cell Biol 113:981–986.PubMedCrossRefGoogle Scholar
  57. Nickoloff BJ, Varani J, Mitra RSJ (1991) Modulation of keratinocyte biology by gamma interferon: relevance to cutaneous wound healing. Prog Clin Biol Res 365:141–154.PubMedGoogle Scholar
  58. O’Connor NE, Mulliken JB, Banks-Schlegel S, Kehinde O, Green H (1981) Grafting of burns with cultured epithelium prepared from autologous epidermal cells. Lancet 1:75–78.CrossRefGoogle Scholar
  59. Odland G, Ross R (1968) Human wound repair. I. Epidermal regeneration. J Cell Biol 39:135–151.PubMedCrossRefGoogle Scholar
  60. O’Keefe EJ, Woodley DT, Castillo G, Russell N, Payne RE (1984) Production of soluble and cell-associated fibronectin in cultured keratinocytes. J Invest Dermatol 82:150–155.PubMedCrossRefGoogle Scholar
  61. O’Keefe EJ, Payne RE, Russell N (1985) Spreading and enhanced motility of human keratinocytes on fibronectin. J Invest Dermatol 85:125–130.PubMedCrossRefGoogle Scholar
  62. Phillips T (1988) Cultured skin grafts: past, present, future. Arch Dermatol 124:1035–1038.PubMedCrossRefGoogle Scholar
  63. Poskitt KR, Lloyd-Davies E, James A, McCollum CN (1985) Does pinch grafting accelerate the healing of chronic venous ulcers?. Br J Surg 72:401–402.CrossRefGoogle Scholar
  64. Potten CS, Morris RJ (1988) Epithelial stem cells in vivo. J Cell Sci 10:45–62.Google Scholar
  65. Pruneiras M, Regnier M, Woodley D (1983) Methods of cultivation of keratinocytes at an air liquid interface. J Invest Dermatol 81:28–33.CrossRefGoogle Scholar
  66. Rheinwald JG, Green H (1975) Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6:331–344.PubMedCrossRefGoogle Scholar
  67. Rheinwald JG, Green H (1977) Epidermal growth factor and multiplication of cultured human epidermal keratinocytes. Nature 265:421–424.PubMedCrossRefGoogle Scholar
  68. Sauder DN, Stanulis-Praeger BM, Gilchrest BA (1988) Autocrine stimulation of human keratinocytes by epidermal cell-derived thymocyte activating factor: implications for skin aging. Arch Dermatol Res 280:71–76.PubMedCrossRefGoogle Scholar
  69. Schultz GS, White M, Mitchell R, Brown G, Lynch J, Twarzdick DR, Todaro GJ (1987) Epithelial wound healing enhanced by transforming growth factor α and vaccinia virus. Science 235:350–352.PubMedCrossRefGoogle Scholar
  70. Shah M, Foreman DM, Ferguson MWF (1992) Control of scarring in adult wounds by neutralising antibody to transforming growth factor β. Lancet 339:213–214.PubMedCrossRefGoogle Scholar
  71. Sporn MB, Roberts AB, Shull JM, Smith JM, Ward JM, Sodek J (1983) Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo. Science 219:1329–1331.PubMedCrossRefGoogle Scholar
  72. Stanley JR, Hawley-Nelson P, Yaar M, Martin GR, Katz SI (1982) Laminin and bullous pemphigoid antigen are distinct basement membrane proteins synthesized by epidermal cells. J Invest Dermatol 78:456–459.PubMedCrossRefGoogle Scholar
  73. Sun T-T, Eichner R, Nelson WG, Tseng SCG, Weiss RA, Jarvinen M, Woodcock-Mitchell J (1983) Keratin classes: molecular markers for different types of epithelial differentiation. J Invest Dermatol 81:109s–115s.PubMedCrossRefGoogle Scholar
  74. Takashima A, Grinnell F (1985) Fibronectin-mediated keratinocyte migration and initiation of fibronectin receptor function. J Invest Dermatol 85:304–308.PubMedCrossRefGoogle Scholar
  75. Tatnall FM, Leigh IM, Gibson JR (1990) Comparative study of antiseptic toxicity on basal keratinocytes, transformed human keratinocytes and fibroblasts. Skin Pharmacol 3:157–163.PubMedCrossRefGoogle Scholar
  76. Timpl R (1989) Structure and biological activity of basement membrane proteins. Eur J Biochem 180:487–502.PubMedCrossRefGoogle Scholar
  77. Van Brunt J, Klausner A (1988) Growth factors speed wound healing. Biotechnology 6:25–30.CrossRefGoogle Scholar
  78. Weinstein GD (1975) On the cell cycle of psoriasis. Br J Dermatol 92:229–230.PubMedCrossRefGoogle Scholar
  79. Weiss RA, Eichner R, Sun T-T (1984) Monoclonal antibody analysis of keratin expression in epidermal diseases: a 48-and 56-kdalton keratin as molecular markers for hyperproliferative keratinocytes. J Cell Biol 98:1397–1406.PubMedCrossRefGoogle Scholar
  80. Whitby DJ, Ferguson MWJ (1991) Immunohistochemical localisation of growth factors in fetal wound healing. Dev Biol 147:207–215.PubMedCrossRefGoogle Scholar
  81. Winter GD (1972) Epidermal regeneration studied in the domestic pig. In: Maibach HI, Rovee DT (eds) Epidermal wound healing. Year Book Medical Publishers, Chicago, pp 71–112.Google Scholar
  82. Withers HR (1967) Recovery and repopulation in vivo by the mouse skin epithelial cells during fractionated irradiation. Radiat Res 32:227–239.PubMedCrossRefGoogle Scholar
  83. Woodley DT, O’Keefe EJ, Prunieras M (1985) Cutaneous wound healing: a model for cellmatrix interactions. J Am Acad Dermatol 12:420–433.PubMedCrossRefGoogle Scholar
  84. Woodley DT, Bachman PM, O’Keefe EJ (1988) Laminin inhibits human keratinocyte migration. J Cell Physiol 136:140–146.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • I. M. Leigh
    • 1
  1. 1.Dept. Experimental DermatologyLondon Hospital Medical CollegeLondonUK

Personalised recommendations