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The influence of differing connective tissue substrates on the maintenance of adult stratified squamous epithelia


The interaction between adult stratified squamous epithelium and its supporting connective tissue possibly involves both permissive and directive influences. To examine the effect of vitality and specificity of connective tissue on the maintenance of epithelial structure and histo-differentiation, specimens of skin and oral mucosa from various regions of adult mice were separated using either EDTA or trypsin. Prior to transplantation, the epithelium was recombined with either inverted homologous connective tissue or with connective tissue that had been killed either by heating or repeated freeze-thawing. Epithelial sheets were also transplanted onto the graft bed alone or in combination with striated muscle or tendon.

Normal patterns of cytodifferentiation were maintained when the epithelium was recombined with inverted or frozen-thawed subepithelial connective tissue but there was a loss of spatial organization on the frozen-thawed connective tissue. In contrast, heat-killed or trypsin-treated frozen-thawed subepithelial connective tissue and non-dermal connective tissue failed to maintain a viable epithelium. These observations suggest that subepithelial connective tissues (dermis, lamina propria) but not deep connective tissues facilitate epithelial proliferation and histodifferentiation.

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  1. Banks-Schlegel S, Green H (1980) Formation of epidermis by serially cultivated human epidermal cells transplanted as an epithelium to athymic mice. Transplantation 29:308–313

  2. Billingham RE, Reynolds J (1952) Transplantation studies on skeets of pure epidermal epithelium and on epidermal cell suspensions. Br J Plast Surg 5:25–36

  3. Billingham RE, Silver WK (1967) Studies on the conservation of epidermal specificities of skin and certain mucosas in adult mammals. J Exp Med 125:429–446

  4. Bordin S, Page R, Narayannan AS (1984) Heterogeneity of normal human diploid fibroblasts: isolation and characterization of one phenotype. Science 223:4632

  5. Briggaman RA, Wheeler CE (1968) Epidermal-dermal interactions in adult human skin: Role of dermis in epidermal maintanance. J Invest Dermatol 51:454–465

  6. Briggaman RA, Wheeler CE (1971) Epidermal-dermal interactions in adult human skin: The nature of the dermal influence. J Invest Dermatol 56:18–26

  7. Christophers E, Laurence EB (1973) Regional variations in mouse skin: Quantitation of epidermal compartments in these different body sites. Virchows Arch [Cell Pathol] 12:212–222

  8. Dodson JW (1967) The differentiation of epidermis. I. The interrelationship of epidermis and dermis in embryonic chicken skin. J Embryol Exp Morphol 17:83–105

  9. Doran TI, Vidrich A, Sun T-T (1980) Intrinsic and extrinsic regulation of the differentiation of skin, corneal and esophageal epithelial cells. Cell 22:17–25

  10. Fuchs E, Green H (1980) Changes in keratin gene expression during terminal differentiation of the keratinocyte. Cell 19:1033–1042

  11. Fusenig NE, Valentine EA, Worst PKM (1980) Growth behavior of normal and transformed mouse epidermal cells after reimplantation in vivo. In: Richards RJ, Rajan KT (eds) Tissue culture in medical research (II). Pergamon Press, Oxford, New York

  12. Fusenig NE, Breitkreutz D, Dzarlieva RT, Boukamp P, Bohnert A, Tilgen W (1983) Growth and differentiation characteristics of transformed keratinocytes from mouse and human skin in vitro and in vivo. J Invest Dermatol 81:168s-175s

  13. Grobstein C (1953) Epithelio-mesenchymal specificity in the morphogenesis of mouse submandibular rudiments in vitro. J Exp Zool 124:383–414

  14. Harris RR, Mackenzie IC, Williams RAD (1980) An examination of the relationship between experimentally altered rates of epidermal proliferation and rates of epidermal metabolism assayed in vitro. J Invest Dermatol 74:402–406

  15. Hassel TM, Stanek EJ (1983) Evidence that healthy human gingiva contains functionally heterogeneous fibroblast subpopulations. Arch Oral Biol 28:617–625

  16. Hay ED (1978) Role of basement membranes in development and differentiation. In: Kefalides NA (ed) Biology and chemistry of basement membrane. Academic Press, NY pp 119–136

  17. Hay ED, Dodson JW (1973) Secretion of collagen by corneal epithelium. J Cell Biol 57:190–213

  18. Hill MW, Mackenzie IC (1982) The influence of deep connective tissue on epithelial migration and differentiation. J Dent Res 61:322 (Abst)

  19. Hill MW, Berg JH, Mackenzie IC (1981) Quantitative evaluation of regional differences between epithelia in the adult mouse. Arch Oral Biol 26:1063–1067

  20. Holbrook KA, Hennings H (1983) Phenotypic expression of epidermal cells in vitro: A review. J Invest Dermatol (In press)

  21. Holmstrup P, Dabelsteen E, Stoltze K, Worsaae N (1981) Epithelial outgrowths from human buccal mucosa transplants in nude mice. Scand J Dent Res 89:417–423

  22. Karasek MA (1968) Growth and differentiation of transplanted epithelial cell cultures. J Invest Dermatol 51:247–252

  23. Karasek MA (1973) Dermal factors affecting epidermal cells in vitro. J Invest Dermatol 59:99–101

  24. Kollar EJ (1966) An in vitro study of hair and vibrissae development in embryonic mouse skin. J Invest Dermatol 46:254–262

  25. Laurence EB (1980) The regulation of cell proliferation in normal epithelia. In: Mackenzie IC, Dabelsteen E, Squier CA (eds) Oral premalignancy. University of Iowa Press pp 164–190

  26. Lavker RM, Sun T-T (1983) Rapid modulation of keratinocyte differentiation by the external environment. J Invest Dermatol 80:228–237

  27. Mackenzie IC, Fusenig NE (1983) Regeneration of organized epithelial structure. J Invest Dermatol 81:189s-194s

  28. Mackenzie IC, Hill MW (1981) Maintenance of regionally-specific patterns of cell proliferation and differentiation in transplanted skin and oral mucosa. Cell Tissue Res 219:597–607

  29. Mackenzie IC, Hill MW (1984) Connective tissue influences on patterns of epithelial architecture and keratinization in skin and oral mucosa of the adult mouse. Cell Tissue Res 235:551–559

  30. McLoughlin CB (1961) The importance of mesenchymal factors in the differentiation of chick epidermis: The differentiation in culture of the isolated epidermis of the embryonic chick. J Embryol Exp Morphol 9:370–384

  31. Melbye SE, Karasek MA (1973) Some characteristics of a factor stimulating skin epithelial growth in vitro. Exp Cell Res 79:279–286

  32. Osman M, Ruch J (1981) Behavior of odontoblasts and basal lamina of trypsin or EDTA-isolated mouse dental papillae in short-term culture. J Dent Res 60:1015–1027

  33. Rheinwald JG (1979) The role of terminal differentiation in the finite culture lifetime of the human epidermal keratinocyte. Int Rev Cytol 10:25–33

  34. Rheinwald JG, Green H (1977) Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes. Nature 265:421–424

  35. Saxen L (1977) Directive versus permissive induction: A working hypothesis. In: Lash JW, Burger MM (eds) Cell and Tissue Interactions. Raven Press, NY

  36. Scaletta LJ, MacCallum DK (1972) A fine structural study of divalent cation mediated epithelial union with connective tissue in human oral mucosa. Am J Anat 133:431–454

  37. Schweizer J, Winter H, Hill MW, Mackenzie IC (1984) The keratin polypeptide patterns in heterotypically recombined epithelia of skin and mucosa of the adult mouse. Differentiation 26:144–153

  38. Sengel P (1976) Morphogenesis of skin. Cambridge University Press, Cambridge, p 68

  39. Terrzaghi M, Klein-Szanto AJP (1980) Differentiation of normal and cultured preneoplastic tracheal epithelial cells in rats: Importance of epithelial mesenchymal interactions. J Natl Cancer Inst 65:1039–1048

  40. Wessels NK (1962) Tissue interactions during skin histodifferentiation. Dev Biol 4:87–107

  41. Wicha MS, Liotta LA, Vonderhaar BK, Kidwell WR (1980) Effects of inhibition of basement membranes collagen deposition on rat mammary gland development. Dev Biol 80:253–266

  42. Woodley D, Regnier M, Prunieras M (1980) In vitro basal lamina formation may require non-epidermal cell living substrate. Br J Dermatol 103:397–404

  43. Worst PKM, Mackenzie IC, Fusenig NE (1982) Reformation of organized epidermal structure by transplantation of suspensions and cultures of epidermal and dermal cells. Cell Tissue Res 225:65–77

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Correspondence to Dr. Murray W. Hill.

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Supported by NIH/NIDR RO1 DEO5190

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Hill, M.W., Mackenzie, I.C. The influence of differing connective tissue substrates on the maintenance of adult stratified squamous epithelia. Cell Tissue Res. 237, 473–478 (1984).

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Key words

  • Skin
  • Oral mucosa
  • Epithelial-mesenchymal
  • interactions
  • Mouse