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. 1996 Jun;148(6):1871–1885.

Fibroblast-dependent induction of a murine skin lesion with similarity to human common blue nevus.

S M Prouty 1, L Lawrence 1, K S Stenn 1
PMCID: PMC1861639  PMID: 8669473

Abstract

In an attempt to define epithelial-mesenchymal interactions in skin appendage formation, we have been studying a nude mouse grafting model that permits the combination of heterotypic and heterochronic epithelial and mesenchymal cells. In this study using neonatal hair bud cells combined with various mesenchymal cell preparations, we show that one can regenerate near-complete skin with intact epidermal and dermal layers plus mature hair follicles. It was determined that the character of the resulting regenerated skin could be manipulated as a function of the specific mesenchymal component. Lack of dermal cells resulted in a scar, whereas inclusion of a suspension of dissociated total dermal cells resulted in near-complete skin regeneration, and in the presence of follicular papilla fibroblasts (both hair-inductive and non-hair-inductive) or NIH3T3 fibroblasts, the reconstitution had similarity to the common blue nevus. The results indicate that 1) a stimulant of human common blue nevus can be produced in an animal model, 2) the underlying disorder of the lesion in mice appears to be entirely dermal in origin, arising independent of the epidermal component, and 3) complex dermal cell interactions involving lesion-initiative and lesion-suppressive activities underlie the pathogenesis. This experimental system will serve as a valuable tool in elucidating cutaneous dermal-epidermal signals in normal skin as well as the alteration of these signals in malformations such as the hamartoma described here.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aaronson S. A., Todaro G. J. Development of 3T3-like lines from Balb-c mouse embryo cultures: transformation susceptibility to SV40. J Cell Physiol. 1968 Oct;72(2):141–148. doi: 10.1002/jcp.1040720208. [DOI] [PubMed] [Google Scholar]
  2. Arase S., Sadamoto Y., Katoh S., Urano Y., Takeda K. Co-culture of human hair follicles and dermal papillae in a collagen matrix. J Dermatol. 1990 Nov;17(11):667–676. doi: 10.1111/j.1346-8138.1990.tb03009.x. [DOI] [PubMed] [Google Scholar]
  3. Billingham R. E., Silvers W. K. Studies on the conservation of epidermal specificies of skin and certain mucosas in adult mammals. J Exp Med. 1967 Mar 1;125(3):429–446. doi: 10.1084/jem.125.3.429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Birchmeier C., Birchmeier W. Molecular aspects of mesenchymal-epithelial interactions. Annu Rev Cell Biol. 1993;9:511–540. doi: 10.1146/annurev.cb.09.110193.002455. [DOI] [PubMed] [Google Scholar]
  5. Blume-Jensen P., Siegbahn A., Stabel S., Heldin C. H., Rönnstrand L. Increased Kit/SCF receptor induced mitogenicity but abolished cell motility after inhibition of protein kinase C. EMBO J. 1993 Nov;12(11):4199–4209. doi: 10.1002/j.1460-2075.1993.tb06104.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bucala R., Spiegel L. A., Chesney J., Hogan M., Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994 Nov;1(1):71–81. [PMC free article] [PubMed] [Google Scholar]
  7. Buffey J. A., Messenger A. G., Taylor M., Ashcroft A. T., Westgate G. E., MacNeil S. Extracellular matrix derived from hair and skin fibroblasts stimulates human skin melanocyte tyrosinase activity. Br J Dermatol. 1994 Dec;131(6):836–842. doi: 10.1111/j.1365-2133.1994.tb08586.x. [DOI] [PubMed] [Google Scholar]
  8. Cepko C. L., Ryder E. F., Austin C. P., Walsh C., Fekete D. M. Lineage analysis using retrovirus vectors. Methods Enzymol. 1993;225:933–960. doi: 10.1016/0076-6879(93)25059-b. [DOI] [PubMed] [Google Scholar]
  9. Cooper M., Pinkus H. Intrauterine transplantation of rat basal cell carcinoma as a model for reconversion of malignant to benign growth. Cancer Res. 1977 Aug;37(8 Pt 1):2544–2552. [PubMed] [Google Scholar]
  10. Dalziel K., Marks R. Hair follicle-like change over histiocytomas. Am J Dermatopathol. 1986 Dec;8(6):462–466. doi: 10.1097/00000372-198612000-00002. [DOI] [PubMed] [Google Scholar]
  11. Farooqui J. Z., Auclair B. W., Robb E., Sarkisian E., Cooper C., Alexander J. W., Warden G., Boissy R. E., Norlund J. Histological, biochemical, and ultrastructural studies on hyperpigmented human skin xenografts. Pigment Cell Res. 1993 Aug;6(4 Pt 1):226–233. doi: 10.1111/j.1600-0749.1993.tb00606.x. [DOI] [PubMed] [Google Scholar]
  12. Farooqui J. Z., Robb E., Boyce S. T., Warden G. D., Nordlund J. J. Isolation of a unique melanogenic inhibitor from human skin xenografts: initial in vitro and in vivo characterization. J Invest Dermatol. 1995 May;104(5):739–743. doi: 10.1111/1523-1747.ep12606972. [DOI] [PubMed] [Google Scholar]
  13. Fields-Berry S. C., Halliday A. L., Cepko C. L. A recombinant retrovirus encoding alkaline phosphatase confirms clonal boundary assignment in lineage analysis of murine retina. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):693–697. doi: 10.1073/pnas.89.2.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Freeman A. E., Gilden R. V., Vernon M. L., Wolford R. G., Hugunin P. E., Huebner R. J. 5-Bromo-2'-deoxyuridine potentiation of transformation of rat-embryo cells induced in vitro by 3-methylcholanthrene: induction of rat leukemia virus gs antigen in transformed cells. Proc Natl Acad Sci U S A. 1973 Aug;70(8):2415–2419. doi: 10.1073/pnas.70.8.2415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Friedrich G., Soriano P. Promoter traps in embryonic stem cells: a genetic screen to identify and mutate developmental genes in mice. Genes Dev. 1991 Sep;5(9):1513–1523. doi: 10.1101/gad.5.9.1513. [DOI] [PubMed] [Google Scholar]
  16. Fukuzawa T., Ide H. A ventrally localized inhibitor of melanization in Xenopus laevis skin. Dev Biol. 1988 Sep;129(1):25–36. doi: 10.1016/0012-1606(88)90158-3. [DOI] [PubMed] [Google Scholar]
  17. Fukuzawa T., Samaraweera P., Mangano F. T., Law J. H., Bagnara J. T. Evidence that MIF plays a role in the development of pigmentation patterns in the frog. Dev Biol. 1995 Jan;167(1):148–158. doi: 10.1006/dbio.1995.1013. [DOI] [PubMed] [Google Scholar]
  18. Goette D. K., Helwig E. B. Basal cell carcinomas and basal cell carcinoma-like changes overlying dermatofibromas. Arch Dermatol. 1975 May;111(5):589–592. [PubMed] [Google Scholar]
  19. Grimwood R. E., Tharp M. D. Growth of human basal cell carcinomas transplanted to C57/Balb/C bgJ/bgJ nu/nu (beige-nude) mice. J Dermatol Surg Oncol. 1991 Aug;17(8):661–666. doi: 10.1111/j.1524-4725.1991.tb01316.x. [DOI] [PubMed] [Google Scholar]
  20. Halaban R., Langdon R., Birchall N., Cuono C., Baird A., Scott G., Moellmann G., McGuire J. Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes. J Cell Biol. 1988 Oct;107(4):1611–1619. doi: 10.1083/jcb.107.4.1611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Handjiski B. K., Eichmüller S., Hofmann U., Czarnetzki B. M., Paus R. Alkaline phosphatase activity and localization during the murine hair cycle. Br J Dermatol. 1994 Sep;131(3):303–310. doi: 10.1111/j.1365-2133.1994.tb08515.x. [DOI] [PubMed] [Google Scholar]
  22. Happle R. Mosaicism in human skin. Understanding the patterns and mechanisms. Arch Dermatol. 1993 Nov;129(11):1460–1470. [PubMed] [Google Scholar]
  23. Hardy M. H. The secret life of the hair follicle. Trends Genet. 1992 Feb;8(2):55–61. doi: 10.1016/0168-9525(92)90350-d. [DOI] [PubMed] [Google Scholar]
  24. Hay E. D. Extracellular matrix alters epithelial differentiation. Curr Opin Cell Biol. 1993 Dec;5(6):1029–1035. doi: 10.1016/0955-0674(93)90088-8. [DOI] [PubMed] [Google Scholar]
  25. Hernandez A. D., Hibbs M. S., Postlethwaite A. E. Establishment of basal cell carcinoma in culture: evidence for a basal cell carcinoma-derived factor(s) which stimulates fibroblasts to proliferate and release collagenase. J Invest Dermatol. 1985 Nov;85(5):470–475. doi: 10.1111/1523-1747.ep12277201. [DOI] [PubMed] [Google Scholar]
  26. Hirai Y., Takebe K., Takashina M., Kobayashi S., Takeichi M. Epimorphin: a mesenchymal protein essential for epithelial morphogenesis. Cell. 1992 May 1;69(3):471–481. doi: 10.1016/0092-8674(92)90448-l. [DOI] [PubMed] [Google Scholar]
  27. Hunter T. Braking the cycle. Cell. 1993 Dec 3;75(5):839–841. doi: 10.1016/0092-8674(93)90528-x. [DOI] [PubMed] [Google Scholar]
  28. Hunzelmann N., Schönherr E., Bonnekoh B., Hartmann C., Kresse H., Krieg T. Altered immunohistochemical expression of small proteoglycans in the tumor tissue and stroma of basal cell carcinoma. J Invest Dermatol. 1995 Apr;104(4):509–513. doi: 10.1111/1523-1747.ep12605979. [DOI] [PubMed] [Google Scholar]
  29. Jahoda C. A. Induction of follicle formation and hair growth by vibrissa dermal papillae implanted into rat ear wounds: vibrissa-type fibres are specified. Development. 1992 Aug;115(4):1103–1109. doi: 10.1242/dev.115.4.1103. [DOI] [PubMed] [Google Scholar]
  30. Jainchill J. L., Aaronson S. A., Todaro G. J. Murine sarcoma and leukemia viruses: assay using clonal lines of contact-inhibited mouse cells. J Virol. 1969 Nov;4(5):549–553. doi: 10.1128/jvi.4.5.549-553.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Jat P. S., Noble M. D., Ataliotis P., Tanaka Y., Yannoutsos N., Larsen L., Kioussis D. Direct derivation of conditionally immortal cell lines from an H-2Kb-tsA58 transgenic mouse. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5096–5100. doi: 10.1073/pnas.88.12.5096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kligman L. H. Luna's technique. A beautiful stain for elastin. Am J Dermatopathol. 1981 Summer;3(2):199–201. doi: 10.1097/00000372-198100320-00014. [DOI] [PubMed] [Google Scholar]
  33. Kollar E. J. The induction of hair follicles by embryonic dermal papillae. J Invest Dermatol. 1970 Dec;55(6):374–378. doi: 10.1111/1523-1747.ep12260492. [DOI] [PubMed] [Google Scholar]
  34. Lichti U., Weinberg W. C., Goodman L., Ledbetter S., Dooley T., Morgan D., Yuspa S. H. In vivo regulation of murine hair growth: insights from grafting defined cell populations onto nude mice. J Invest Dermatol. 1993 Jul;101(1 Suppl):124S–129S. doi: 10.1111/1523-1747.ep12363165. [DOI] [PubMed] [Google Scholar]
  35. Link R. E., Paus R., Stenn K. S., Kuklinska E., Moellmann G. Epithelial growth by rat vibrissae follicles in vitro requires mesenchymal contact via native extracellular matrix. J Invest Dermatol. 1990 Aug;95(2):202–207. doi: 10.1111/1523-1747.ep12478002. [DOI] [PubMed] [Google Scholar]
  36. Malhotra R., Stenn K. S., Fernandez L. A., Braverman I. M. Angiogenic properties of normal and psoriatic skin associate with epidermis, not dermis. Lab Invest. 1989 Aug;61(2):162–165. [PubMed] [Google Scholar]
  37. Matsui Y., Zsebo K. M., Hogan B. L. Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit. Nature. 1990 Oct 18;347(6294):667–669. doi: 10.1038/347667a0. [DOI] [PubMed] [Google Scholar]
  38. Miller M. W., Duhl D. M., Vrieling H., Cordes S. P., Ollmann M. M., Winkes B. M., Barsh G. S. Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the lethal yellow mutation. Genes Dev. 1993 Mar;7(3):454–467. doi: 10.1101/gad.7.3.454. [DOI] [PubMed] [Google Scholar]
  39. Motro B., van der Kooy D., Rossant J., Reith A., Bernstein A. Contiguous patterns of c-kit and steel expression: analysis of mutations at the W and Sl loci. Development. 1991 Dec;113(4):1207–1221. doi: 10.1242/dev.113.4.1207. [DOI] [PubMed] [Google Scholar]
  40. Muskavitch M. A. Delta-notch signaling and Drosophila cell fate choice. Dev Biol. 1994 Dec;166(2):415–430. doi: 10.1006/dbio.1994.1326. [DOI] [PubMed] [Google Scholar]
  41. Nickoloff B. J., Kunkel S. L., Burdick M., Strieter R. M. Severe combined immunodeficiency mouse and human psoriatic skin chimeras. Validation of a new animal model. Am J Pathol. 1995 Mar;146(3):580–588. [PMC free article] [PubMed] [Google Scholar]
  42. Oliver R. F. The experimental induction of whisker growth in the hooded rat by implantation of dermal papillae. J Embryol Exp Morphol. 1967 Aug;18(1):43–51. [PubMed] [Google Scholar]
  43. PINKUS H. EPITHELIAL AND FIBROEPITHELIAL TUMORS. Arch Dermatol. 1965 Jan;91:24–37. doi: 10.1001/archderm.1965.01600070030003. [DOI] [PubMed] [Google Scholar]
  44. Pisansarakit P., Moore G. P. Induction of hair follicles in mouse skin by rat vibrissa dermal papillae. J Embryol Exp Morphol. 1986 Jun;94:113–119. [PubMed] [Google Scholar]
  45. Pontén F., Ren Z., Nistér M., Westermark B., Pontén J. Epithelial-stromal interactions in basal cell cancer: the PDGF system. J Invest Dermatol. 1994 Mar;102(3):304–309. doi: 10.1111/1523-1747.ep12371787. [DOI] [PubMed] [Google Scholar]
  46. Poole T. W., Silvers W. K. The development of regional pigmentation patterns in black and tan (at) mice. J Exp Zool. 1976 Jul;197(1):115–119. doi: 10.1002/jez.1401970113. [DOI] [PubMed] [Google Scholar]
  47. Qian F., Vaux D. L., Weissman I. L. Expression of the integrin alpha 4 beta 1 on melanoma cells can inhibit the invasive stage of metastasis formation. Cell. 1994 May 6;77(3):335–347. doi: 10.1016/0092-8674(94)90149-x. [DOI] [PubMed] [Google Scholar]
  48. Reynolds A. J., Jahoda C. A. Cultured dermal papilla cells induce follicle formation and hair growth by transdifferentiation of an adult epidermis. Development. 1992 Jun;115(2):587–593. doi: 10.1242/dev.115.2.587. [DOI] [PubMed] [Google Scholar]
  49. Reynolds A. J., Oliver R. F., Jahoda C. A. Dermal cell populations show variable competence in epidermal cell support: stimulatory effects of hair papilla cells. J Cell Sci. 1991 Jan;98(Pt 1):75–83. doi: 10.1242/jcs.98.1.75. [DOI] [PubMed] [Google Scholar]
  50. Rogers G., Martinet N., Steinert P., Wynn P., Roop D., Kilkenny A., Morgan D., Yuspa S. H. Cultivation of murine hair follicles as organoids in a collagen matrix. J Invest Dermatol. 1987 Oct;89(4):369–379. doi: 10.1111/1523-1747.ep12471760. [DOI] [PubMed] [Google Scholar]
  51. Rogers G., Martinet N., Steinert P., Wynn P., Roop D., Kilkenny A., Morgan D., Yuspa S. H. Cultivation of murine hair follicles as organoids in a collagen matrix. J Invest Dermatol. 1987 Oct;89(4):369–379. doi: 10.1111/1523-1747.ep12471760. [DOI] [PubMed] [Google Scholar]
  52. Schellander F., Marks R. The epidermal response to subepidermal inflammation. An experimental study. Br J Dermatol. 1973 Apr;88(4):363–367. doi: 10.1111/j.1365-2133.1973.tb07566.x. [DOI] [PubMed] [Google Scholar]
  53. Schwindinger W. F., Francomano C. A., Levine M. A. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5152–5156. doi: 10.1073/pnas.89.11.5152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Scott G., Ewing J., Ryan D., Abboud C. Stem cell factor regulates human melanocyte-matrix interactions. Pigment Cell Res. 1994 Feb;7(1):44–51. doi: 10.1111/j.1600-0749.1994.tb00017.x. [DOI] [PubMed] [Google Scholar]
  55. Smola H., Thiekötter G., Fusenig N. E. Mutual induction of growth factor gene expression by epidermal-dermal cell interaction. J Cell Biol. 1993 Jul;122(2):417–429. doi: 10.1083/jcb.122.2.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Stenn K. S., Fernandez L. A., Tirrell S. J. The angiogenic properties of the rat vibrissa hair follicle associate with the bulb. J Invest Dermatol. 1988 Mar;90(3):409–411. doi: 10.1111/1523-1747.ep12456517. [DOI] [PubMed] [Google Scholar]
  57. Stenn K. S., Prouty S. M., Seiberg M. Molecules of the cycling hair follicle--a tabulated review. J Dermatol Sci. 1994 Jul;7 (Suppl):S109–S124. doi: 10.1016/0923-1811(94)90042-6. [DOI] [PubMed] [Google Scholar]
  58. Sternberg P. W. Intercellular signaling and signal transduction in C. elegans. Annu Rev Genet. 1993;27:497–521. doi: 10.1146/annurev.ge.27.120193.002433. [DOI] [PubMed] [Google Scholar]
  59. VAN SCOTT E. J., REINERTSON R. P. The modulating influence of stromal environment on epithelial cells studied in human autotransplants. J Invest Dermatol. 1961 Feb;36:109–131. [PubMed] [Google Scholar]
  60. Wagner S. N., Ruhri C., Kunth K., Holecek B. U., Goos M., Höfler H., Atkinson M. J. Expression of stromelysin 3 in the stromal elements of human basal cell carcinoma. Diagn Mol Pathol. 1992 Sep;1(3):200–205. [PubMed] [Google Scholar]
  61. Wehrle-Haller B., Weston J. A. Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway. Development. 1995 Mar;121(3):731–742. doi: 10.1242/dev.121.3.731. [DOI] [PubMed] [Google Scholar]
  62. Weinberg R. A. Tumor suppressor genes. Science. 1991 Nov 22;254(5035):1138–1146. doi: 10.1126/science.1659741. [DOI] [PubMed] [Google Scholar]
  63. Weinberg W. C., Goodman L. V., George C., Morgan D. L., Ledbetter S., Yuspa S. H., Lichti U. Reconstitution of hair follicle development in vivo: determination of follicle formation, hair growth, and hair quality by dermal cells. J Invest Dermatol. 1993 Mar;100(3):229–236. doi: 10.1111/1523-1747.ep12468971. [DOI] [PubMed] [Google Scholar]
  64. Williams D., Profeta K., Stenn K. S. Isolation and culture of follicular papillae from murine vibrissae: an introductory approach. Br J Dermatol. 1994 Mar;130(3):290–297. doi: 10.1111/j.1365-2133.1994.tb02923.x. [DOI] [PubMed] [Google Scholar]
  65. Young H. E., Ceballos E. M., Smith J. C., Mancini M. L., Wright R. P., Ragan B. L., Bushell I., Lucas P. A. Pluripotent mesenchymal stem cells reside within avian connective tissue matrices. In Vitro Cell Dev Biol Anim. 1993 Sep;29A(9):723–736. doi: 10.1007/BF02631429. [DOI] [PubMed] [Google Scholar]
  66. Zambruno G., Marchisio P. C., Melchiori A., Bondanza S., Cancedda R., De Luca M. Expression of integrin receptors and their role in adhesion, spreading and migration of normal human melanocytes. J Cell Sci. 1993 May;105(Pt 1):179–190. doi: 10.1242/jcs.105.1.179. [DOI] [PubMed] [Google Scholar]

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