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Stem cell factor, a novel cutaneous growth factor for mast cells and melanocytes

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Abstract

Mechanisms affecting mast cell and melanocyte growth and function are still poorly understood. This report summarizes the current state of knowledge on a recently described growth factor for both these cell types and for primitive haematopoietic stem cells. Stem cell factor (SCF), also named mast cell growth factor or kit-ligand, has only recently been cloned and has been shown to be encoded on human chromosome 12. It may be of specific importance in cutaneous physiology and pathology since it is produced by several cell types in the skin (e.g. fibroblasts, keratinocytes, endothelial cells) and since it affects melanocyte and mast cell growth, survival, secretion and adhesion as well as migration into tissues. Defects in the genes encoding for the SCF receptor (c-kit-protein) have been shown to be responsible for human piebaldism. A pathogenetic role in mastocytosis has recently been proposed, but remains to be proven. SCF receptor expression is decreased on cells of some malignant cell lines compared to their physiological counterparts, making it unlikely that SCF is a key factor in malignant transformation and cellular hyperproliferation. In haematopoiesis, SCF acts primarily in concert with other growth factors, and we show here that alone in serum-free culture it has no effect on mast cell growth. Furthermore, there is evidence that besides SCF, additional mast cell growth factors are secreted by fibroblasts and keratinocytes, suggesting a complex orchestration of several growth factors in the regulation of cutaneous growth and differentiation in which SCF plays only one part.

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References

  1. Möller A, Czarnetzki BM (1993) Epidermal cytokines and mast cells. In: Luger T, Schwarz T (eds) Epidermal cytokines. Marcel Dekker, New York, pp 377–394

    Google Scholar 

  2. Williams DE, Lyman SD (1991) Molecular and cellular biology of mast cell growth factor: the gene product of the murine steel locus. Behring Inst Mitt 90: 23–27

    Google Scholar 

  3. Copeland NG, Gilbert D, Cho B, Donavan P, Jenkins N, Cosman D, Anderson D, Lyman SD, Williams DE (1990) Mast cell growth factor maps near the steel locus on mouse chromosome 10 and is deleted in a number of steel alleles. Cell 63: 175–183

    Google Scholar 

  4. Zsebo KM, Wypych J, McNiece IK, Lu HS, Smith KA, Karkare SB, Sachdev RK, Yuschenkoff VN, Birkett NC, Williams LR, Satyagal VN, Tung W, Bosselman RA, Mendiaz EA, Langley KE (1990) Identification, purification and biological characterization of hematopoietic stem cell factor from buffalo rat liver-conditioned medium. Cell 63: 195–201

    Google Scholar 

  5. Huang E, Nocka K, Beier DR, Chu T-Y, Buck J, Lahm H-W, Wellner D, Leder P, Besmer P (1990) The hematopoietic growth factor KL is encoded at the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 63: 225–233

    Google Scholar 

  6. Chabot B, Stephenson DA, Chapman VM, Besmer O, Bernstein A (1988) The protooncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature 335: 88–89

    Google Scholar 

  7. Zsebo KM, Williams DA, Geisler EN, Broudy VC, Martin FH, Atkins HL, Hsu RY, Birkett NC, Okino KH, Murdock DC (1990) Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 63: 213–224

    Google Scholar 

  8. Anderson DM, Lyman SD, Baird A, Wignall JM, Eisenman J, Rauch C, March CJ, Boswell HS, Gimpel SD, Cosman D, Williams DE (1990) Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell 63: 235–243

    Google Scholar 

  9. Dolci S, Williams DE, Ernst MK, Resnick JL, Brannan CI, Lock LF, Lyman SD, Boswell HS, Donovan PJ (1991) Requirement for mast cell growth factor for primordial germ cell survival in culture. Nature 352: 809–811

    Google Scholar 

  10. Qui F-H, Ray P, Brown K, Barker PE, Jhanwar S, Ruddle FH, Besmer P (1988) Primary structure of c-kit: relationship with the CSF-1/PDGF receptor kinase family — oncogenic activation of c-kit involves deletion of extracellular domain and c-terminus. EMBO J 7: 1003–1011

    Google Scholar 

  11. Ruta M, Burgess W, Givol D, Epstein J, Neiger N, Kaplow J, Crumley G, Dionne C, Jaye M, Schlessinger J (1989) Receptor for acidic fibroblast growth factor is related to the tyrosine kinase encoded for the fms-like gene (FLG). Proc Natl Acad Sci USA 86: 8722–8726

    Google Scholar 

  12. Lev S, Yarden Y, Givol D (1992) Dimerization and activation of the kit receptor by monovalent and bivalent binding of the stem cell factor. J Biol Chem 267: 15970–15977

    Google Scholar 

  13. Yee NS, Langen H, Besmer P (1993) Mechanism of kit ligand, phorbol ester, and calcium-induced down-regulation of c-kit receptors in mast cells. J Biol Chem 268: 14189–14201

    Google Scholar 

  14. Welham MJ, Schrader JW (1992) Steel factor-induced tyrosine phosphorylation in murine mast cells. Common elements with IL-3-induced signal transduction pathways. J Immunol 149: 2772–2783

    Google Scholar 

  15. Iwamoto T, Takahashi M, Ohbayashi M, Nakashima I (1992) The ret oncogene can induce melanogenesis and melanocyte development in Wv/Wv mice. Exp Cell Res 200: 410–415

    Google Scholar 

  16. Tan JC, Nocka K, Ray P, Traktman P, Besmer P (1990) The dominant W42 spotting phenotype results from a missense mutation in the c-kit receptor kinase. Science 247: 209–212

    Google Scholar 

  17. Kitamura Y, Go S (1979) Decreased production of mast cells in Sl/Sld anemic mice. Blood 53: 492–497

    Google Scholar 

  18. Reisbach G, Bartke I, Kempkes B, Kostka G, Ellwart J, Birner A, Thalmeier K, Mailhammer R, Bornkamm GW, Ullrich A (1993) Characterization of hemopoietic cell populations from human cord blood expressing c-kit. Exp Hematol 21: 74–79

    Google Scholar 

  19. Inui S, Sakaguchi N (1992) Establishment of a murine pre-B cell clone dependent on interleukin-7 and stem cell factor. Immunol Lett 34: 279–288

    Google Scholar 

  20. Longley BJ, Morganroth GS, Tyrell BA, Tie Gang Ding, Anderson DM, Williams DE, Halaban R (1993) Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis. N Engl J Med 328: 1302–1307

    Google Scholar 

  21. Katayama I, Yokozeke H, Nishioka K (1993) Induction and characterization of mast cell colonies by culture supernatant of retinoic acid-treated mouse keratinocytes. Int Arch Allergy Immunol 100: 328–332

    Google Scholar 

  22. Hamann K, Haas N, Grabbe J, Czarnetzki BM (1994) Expression of stem cell factor in cutaneous mastocytosis. Br J Dermatol (in press)

  23. Tsuji K, Lyman SD, Sudo T, Clark SC, Ogawa M (1992) Enhancement of murine hematopoiesis by synergistic interactions between steel factor (ligand for c-kit), interleukin-11, and other early acting factors in culture. Blood 79: 2855–2860

    Google Scholar 

  24. Lowry PA, Deacon D, Whitefiled P, McGrawth HE (1992) Stem cell factor induction of in vitro murine hematopoietic colony formation by “subliminal” cytokine combinations: the role of “anchor factors”. Blood 80: 663–669

    Google Scholar 

  25. Tanaka R, Koike K, Imai T, Shiohara M, Kubo T, Amano Y, Komiyama A, Nakahata T (1992) Stem cell factor enhances proliferation, but not maturation of murine megakaryocytic progenitors in serum-free culture. Blood 80: 1743–1749

    Google Scholar 

  26. Cicuttini FM, Begley CG, Boyd AW (1992) The effect of recombinant stem cell factor (SCF) on purified CD34-positive human umbilical cord blood progenitor cells. Growth Factors 6: 31–39

    Google Scholar 

  27. Bodine DM, Orlic D, Birkett NC, Seidel NE, Zsebo KM (1992) Stem cell factor increases colony-forming unit-spleen number in vitro in synergy with interleukin-6, and in vivo in Sl/Sld mice as a single factor. Blood 79: 913–919

    Google Scholar 

  28. Meininger CJ, Yano H, Rottapel R, Bernstein A, Zsebo KM, Zetter BR (1992) The c-kit receptor ligand functions as a mast cell chemoattractant. Blood 79: 958–963

    Google Scholar 

  29. Miura N, Okada S, Zsebo KM, Miura Y, Suda T (1993) Rat stem cell factor and IL-6 preferentially support the proliferation of c-kit positive murine hemopoietic cells rather than their differentiation. Exp Hematol 21: 143–149

    Google Scholar 

  30. Avraham H, Scadden DT, Chi S, Broudy VC, Zsebo KM, Groopman JE (1992) Interaction of human bone marrow fibroblasts with megakaryoctes: role of the c-kit ligand. Blood 80: 1679–1684

    Google Scholar 

  31. Ducharme LA, Weis JH (1992) Modulation of integrin expression during mast cell differentiation. Eur J Immunol 22: 2603–2607

    Google Scholar 

  32. Luskey BD, Rosenblatt M, Zsebo K, Williams DA (1992) Stem cell factor, interleukin-3, and interleukin-6 promote retroviralmediated gene transfer into murine hematopoietic stem cells. Blood 80: 396–402

    Google Scholar 

  33. Andrews RG, Bartelmez SH, Knitter GH, Myerson GH, Bernstein ID, Appelbaum FR, Zsebo KM (1992) A c-kit ligand, recombinant human stem cell factor, mediates reversible expansion of multiple CD34+ colony-forming cell types in blood and marrow of baboons. Blood 80: 920–927

    Google Scholar 

  34. McNiece IK, Bertoncello I, Keller JR, Ruscetti FW, Hartley CA, Zsebo KM (1992) Transforming growth factor beta inhibits the action of stem cell factor on mouse and human hematopoietic progenitors. Int J Cell Cloning 10: 80–86

    Google Scholar 

  35. Budel LM, Delwel R, van-Buitenen C, Hoogerbrugge H, Lowenberg B (1993) Effects of mast cell growth factor on acute myeloid leukemia cells in vitro: effects of combinations with other cytokines. Leukemia 7: 426–434

    Google Scholar 

  36. Sillaber C, Strobl H, Bevec D, Ashman LK, Butterfield JH, Lechner K, Maurer D, Bettelheim P, Valent P (1991) IL-4 regulates c-kit proto-oncogene product expression in human mast and myeloid progenitor cells. J Immunol 147: 4224–4228

    Google Scholar 

  37. Rossi P, Dolci S, Albanesi C, Grimaldi P, Ricca R, Geremia R (1993) Follicle-stimulating hormone induction of steel factor (SLF) mRNA in mouse Sertoli cells and stimulation of DNA synthesis in spermatogonia by soluble SLF. Dev Biol 155: 68–74

    Google Scholar 

  38. Keller G, Kennedy M, Papayannopoulou T, Wiles MV (1993) Hematiopoietic commitment during embryonic stem cell differentiation. Mol Cell Biol 13: 473–486

    Google Scholar 

  39. Ginsburg H, Lagunoff D (1967) The in vitro differentiation of mast cells. Cultures of cells from immunized mouse lymphnodes and thoracic duct lymph on fibroblast monolayers. J Cell Biol 35: 685–690

    Google Scholar 

  40. Czarnetzki BM, Figdor CG, Kolde G, Vroom T, Aalberse R, de Vries JE (1984) Development of human connective tissue mast cells from purified blood monocytes. Immunology 51: 549–554

    Google Scholar 

  41. Kitamura Y, Go S, Hatanaka S (1978) Decrease of mast cells in W/WV mice and their increase in bone marrow transplantation. Blood 52: 447–452

    Google Scholar 

  42. Haylock DN, To LB, Dowse TL, Juttner CA, Simmons PJ (1992) Ex vivo expansion and maturation of peripheral blood CD34+ cells into the myeloid lineage. Blood 80: 1405–1412

    Google Scholar 

  43. Schuening FG, Appelbaum FR, Deeg HJ, Sullican-Pepe M, Graham TC, Hackman R (1993) Effects of recombinant canine stem cell factor, a c-kit ligand, and recombinant granulocyte colony-stimulating factor on haematopoietic recovery after otherwise lethal total body irradiation. Blood 81: 20–26

    Google Scholar 

  44. Kirshenbaum AS, Goff JP, Kessler SW, Mican JM, Zsebo KM, Metcalfe DD (1992) Effect of IL-3 and stem cell factor on the appearance of human basophils and mast cells from CD34+ pluripotent progenitor cells. J Immunol 148: 772–777

    Google Scholar 

  45. Mitsui H, Furitsu T, Dvorak AM, Irani A-MA, Schwartz LB, Inagaki N, Takei M, Ishizaka K, Zsebo KM, Gillis S, Ishizaka T (1993) Development of human mast cells from umbilical cord blood cells by recombinant human and murine c-kit ligand. Proc Natl Acad Sci USA 90: 735–739

    Google Scholar 

  46. Kirshenbaum AS, Kessler SW, Goff JP, Metcalfe DD (1991) Demonstration of the origin of human mast cells from CD34+ bone marrow progenitor cells. J Immunol 146: 1410–1415

    Google Scholar 

  47. Welker P, Grabbe J, Hakimi J, Walls AF, Ostmeier H, Czarnetzki BM (1992) Fibroblast-derived factors induce different mast cell characteristics in human myeloid cell lines and peripheral monocytes. Int Arch Allergy Immunol 99: 337–339

    Google Scholar 

  48. Hamann K, Grabbe J, Welker P, Haas N, Algermissen B, Czarnetzki BM (1994) Phenotypic evaluation of cultured human mast cells and of normal human skin mast cells. Arch Dermatol Res 286: 380–385

    Google Scholar 

  49. Grabbe J, Welker P, Möller A, Dippel E, Ashman LF, Czarnetzki BM (1994) Comparative cytokine release from human monocytes, monocyte-derived immature mast cells and a human mast cell line (HMC1). J Invest Dermatol (in press)

  50. Columbo M, Horowitz EM, Botana LM, MacGlashan DW, Bochner BS, Gillis S, Zsebo KM, Galli SJ, Lichtenstein LM (1992) The human recombinant c-kit receptor ligand, rhSCF, induces mediator release from human cutaneous mast cells and enhances IgE-dependent mediator release from both human skin mast cells and peripheral basophils. J Immunol 149: 599–608

    Google Scholar 

  51. Nakajima K, Hirai K, Yamaguchi M, Takaishi T, Ohta K, Morita Y, Ito K (1992) Stem cell factor has histamine releasing activity in rat connective tissue-type mast cells. Biochem Biophys Res Commun 183: 1076–1083

    Google Scholar 

  52. Coleman JW, Holliday MR, Kimber I, Zsebo KM, Galli SJ (1993) Regulation of mouse peritoneal mast cell secretory function by stem cell factor. J Immunol 150: 556–562

    Google Scholar 

  53. Bischoff SC, Dahinden CA (1992) c-kit ligand: a unique potentiator of mediator release by human lung mast cells. J Exp Med 175: 237–244

    Google Scholar 

  54. Kuna P, Reddigari SR, Schall TJ, Rucinski D, Sadick M, Kaplan AP (1993) Characterization of the human basophil response to cytokines, growth factors, and histamine releasing factors of the intercrine/chemokine family. J Immunol 150: 1932–1943

    Google Scholar 

  55. Wershil BK, Tsai M, Geissler EN, Zsebo KM, Galli SJ (1992) The rat c-kit ligand, stem cell factor, induces c-kit receptor-dependent mouse mast cell activation in vivo. Evidence that signaling through the c-kit receptor can induce expression of cellular function. J Exp Med 175: 245–255

    Google Scholar 

  56. Galli SJ, Temura A, Garlick DS, Gamba-Vitalo C, Zsebo KM, Andrews RG (1993) Reversible expansion of primate mast cell populations in vivo by stem cell factor. J Clin Invest 91: 148–152

    Google Scholar 

  57. Dstych J, Metcalfe DD (1994) Stem cell factor induces mast cell adhesion to fibronectin. J Immunol 152: 213–219

    Google Scholar 

  58. Dippel E, Haas N, Hamann K, Grabbe J, Schadendorf D, Czarnetzki BM (1994) Expression of the c-kit receptor in hypomelanosis: a comparative study between piebaldism, nevus pigmentosus and vitiligo. Br J Dermatol (in press)

  59. Funasaka Y, Boulton T, Cobb M (1992) c-Kit-kinase induces a cascade of protein tyrosine phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogen-activated protein kinase but is down-regulated by melanosomes. Mol Biol Cell 3: 197–209

    Google Scholar 

  60. Halaban R, Moellmann G (1993) White mutants in mice shedding light on humans. J Invest Dermatol 100: 176S-185S

    Google Scholar 

  61. Hulten J (1987) Pigment loss and mental retardation. J Med Genet 24: 568–571

    Google Scholar 

  62. Fleischman RA, Saltman DL, Stastny V, Zneimer S (1991) Deletion of the c-kit protooncogene in the human developmental defect piebald trait. Proc Natl Acad Sci USA 88: 10885–10889

    Google Scholar 

  63. Spritz RA, Holmes SA, Berg SZ, Nordlund JJ, Fukai K (1993) Recurrent deletion in the KIT (mast/stem cell growth factor receptor) proto-oncogene is a frequent cause of human piebaldism. Hum Mol Genet 9: 1499–1500

    Google Scholar 

  64. Fleischman RA (1992) Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene. J Clin Invest 89: 1713–1717

    Google Scholar 

  65. Worm M, Reichert U, Czarnetzi BM, Schadendorf D (1993) Expression of growth factor receptors on human melanoma cells — Comparison of modulating effects by interferons and retinoids. Exp Dermatol 2: 217–223

    Google Scholar 

  66. Natali PG, Nicotra MR, Winkler AB, Cavaliere R, Bigotti A, Ullrich A (1992) Progression of human cutaneous melanoma is associated with loss of expression of c-kit proto-oncogene receptors. Int J Cancer 52: 197–201

    Google Scholar 

  67. Lassam N, Bickford S (1992) Loss of c-kit expression in cultured melanoma cells. Oncogene 7: 51–56

    Google Scholar 

  68. Arguello F, Furlanetto RW, Baggs RB, Graves BT, Harwell SE, Cohen HJ, Frantz CN (1992) Incidence and distribution of experimental metastases in mutant mice with defective organ microenvironments (genotypes Sl/Sld and W/Wv). Cancer Res 52: 2304–2309

    Google Scholar 

  69. Grencis RK, Else KJ, Huntley JF, Nishikawa SI (1993) The in vivo role of stem cell factor (c-kit ligand) on mastocytosis and host protective immunity to the intestinal nematode Trichinella spiralis in mice. Parasite Immunol 15: 55–59

    Google Scholar 

  70. Cairo MS, Gillan ER, Weinthal J, Yancik S, van den Ven C, Ho W, Shen V, Buzby JS, Suen Y (1993) Decreased endogenous circulating Steel factor (SLF) levels following allogeneic and autologous BMT: lack of an inverse correlation with post-BMT myeloid engraftment. Bone Marrow Transplant 11: 155–161

    Google Scholar 

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  1. Department of Dermatology, University Clinics Rudolf Virchow, Free University, Augustenburgerplatz 1, D-13344, Berlin, Germany

    J. Grabbe, P. Welker, E. Dippel & B. M. Czarnetzki

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Grabbe, J., Welker, P., Dippel, E. et al. Stem cell factor, a novel cutaneous growth factor for mast cells and melanocytes. Arch Dermatol Res 287, 78–84 (1994). https://doi.org/10.1007/BF00370723

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