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. 1995 Apr 1;181(4):1357–1363. doi: 10.1084/jem.181.4.1357

The FLT3 ligand potently and directly stimulates the growth and expansion of primitive murine bone marrow progenitor cells in vitro: synergistic interactions with interleukin (IL) 11, IL-12, and other hematopoietic growth factors

PMCID: PMC2191974  PMID: 7535335

Abstract

The recently cloned murine flt3 ligand (FL) was studied for its ability to stimulate the growth of primitive (Lin-Sca-1+) and more committed (Lin-Sca-1-) murine bone marrow progenitor cells, alone and in combination with other hematopoietic growth factors (HGFs). Whereas FL was a weak proliferative stimulator alone, it potently synergized with a number of other HGFs, including all four colony-stimulating factor (CSF), interleukin (IL) 6, IL-11, IL-12, and stem cell factor (SCF), to promote the colony formation of Lin-Sca-1+, but not Lin-Sca-1- or erythroid progenitor cells. The synergistic activity of FL was concentration dependent, with maximum stimulation occurring at 250 ng/ml, and was observed when cells were plated at a concentration of one cell per culture, suggesting that its effects are directly mediated. 2 wk of treatment with FL in combination with IL-3 or SCF resulted in the production of a high proportion of mature myeloid cells (granulocytes and macrophages), whereas the combination of FL with G- CSF, IL-11, or IL-12 resulted predominantly in the formation of cells with an immature blast cell appearance. Accordingly, FL in combination with G-CSF or IL-11 expanded the number of progenitors more than 40- fold after 2 wk incubation. Thus, FL emerges as a potent synergistic HGF, that in combination with numerous other HGFs, can directly stimulate the proliferation, myeloid differentiation, and expansion of primitive hematopoietic progenitor cells.

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Selected References

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  1. Bradley T. R., Hodgson G. S. Detection of primitive macrophage progenitor cells in mouse bone marrow. Blood. 1979 Dec;54(6):1446–1450. [PubMed] [Google Scholar]
  2. Chabot B., Stephenson D. A., Chapman V. M., Besmer P., Bernstein A. The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature. 1988 Sep 1;335(6185):88–89. doi: 10.1038/335088a0. [DOI] [PubMed] [Google Scholar]
  3. Galli S. J., Zsebo K. M., Geissler E. N. The kit ligand, stem cell factor. Adv Immunol. 1994;55:1–96. doi: 10.1016/s0065-2776(08)60508-8. [DOI] [PubMed] [Google Scholar]
  4. Geissler E. N., Ryan M. A., Housman D. E. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell. 1988 Oct 7;55(1):185–192. doi: 10.1016/0092-8674(88)90020-7. [DOI] [PubMed] [Google Scholar]
  5. Hannum C., Culpepper J., Campbell D., McClanahan T., Zurawski S., Bazan J. F., Kastelein R., Hudak S., Wagner J., Mattson J. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature. 1994 Apr 14;368(6472):643–648. doi: 10.1038/368643a0. [DOI] [PubMed] [Google Scholar]
  6. Hestdal K., Ruscetti F. W., Ihle J. N., Jacobsen S. E., Dubois C. M., Kopp W. C., Longo D. L., Keller J. R. Characterization and regulation of RB6-8C5 antigen expression on murine bone marrow cells. J Immunol. 1991 Jul 1;147(1):22–28. [PubMed] [Google Scholar]
  7. Heyworth C. M., Whetton A. D., Nicholls S., Zsebo K., Dexter T. M. Stem cell factor directly stimulates the development of enriched granulocyte-macrophage colony-forming cells and promotes the effects of other colony-stimulating factors. Blood. 1992 Nov 1;80(9):2230–2236. [PubMed] [Google Scholar]
  8. Huang E., Nocka K., Beier D. R., Chu T. Y., Buck J., Lahm H. W., Wellner D., Leder P., Besmer P. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell. 1990 Oct 5;63(1):225–233. doi: 10.1016/0092-8674(90)90303-v. [DOI] [PubMed] [Google Scholar]
  9. Jacobsen S. E., Veiby O. P., Smeland E. B. Cytotoxic lymphocyte maturation factor (interleukin 12) is a synergistic growth factor for hematopoietic stem cells. J Exp Med. 1993 Aug 1;178(2):413–418. doi: 10.1084/jem.178.2.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lyman S. D., James L., Johnson L., Brasel K., de Vries P., Escobar S. S., Downey H., Splett R. R., Beckmann M. P., McKenna H. J. Cloning of the human homologue of the murine flt3 ligand: a growth factor for early hematopoietic progenitor cells. Blood. 1994 May 15;83(10):2795–2801. [PubMed] [Google Scholar]
  11. Lyman S. D., James L., Vanden Bos T., de Vries P., Brasel K., Gliniak B., Hollingsworth L. T., Picha K. S., McKenna H. J., Splett R. R. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell. 1993 Dec 17;75(6):1157–1167. doi: 10.1016/0092-8674(93)90325-k. [DOI] [PubMed] [Google Scholar]
  12. Matthews W., Jordan C. T., Wiegand G. W., Pardoll D., Lemischka I. R. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell. 1991 Jun 28;65(7):1143–1152. doi: 10.1016/0092-8674(91)90010-v. [DOI] [PubMed] [Google Scholar]
  13. McNiece I. K., Bertoncello I., Kriegler A. B., Quesenberry P. J. Colony-forming cells with high proliferative potential (HPP-CFC). Int J Cell Cloning. 1990 May;8(3):146–160. doi: 10.1002/stem.5530080302. [DOI] [PubMed] [Google Scholar]
  14. Metcalf D. Hematopoietic regulators: redundancy or subtlety? Blood. 1993 Dec 15;82(12):3515–3523. [PubMed] [Google Scholar]
  15. Metcalf D., Nicola N. A. Direct proliferative actions of stem cell factor on murine bone marrow cells in vitro: effects of combination with colony-stimulating factors. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6239–6243. doi: 10.1073/pnas.88.14.6239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Migliaccio G., Migliaccio A. R., Valinsky J., Langley K., Zsebo K., Visser J. W., Adamson J. W. Stem cell factor induces proliferation and differentiation of highly enriched murine hematopoietic cells. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7420–7424. doi: 10.1073/pnas.88.16.7420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Moore M. A. Review: Stratton Lecture 1990. Clinical implications of positive and negative hematopoietic stem cell regulators. Blood. 1991 Jul 1;78(1):1–19. [PubMed] [Google Scholar]
  18. Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood. 1993 Jun 1;81(11):2844–2853. [PubMed] [Google Scholar]
  19. Rosnet O., Marchetto S., deLapeyriere O., Birnbaum D. Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene. 1991 Sep;6(9):1641–1650. [PubMed] [Google Scholar]
  20. Sherr C. J., Rettenmier C. W., Sacca R., Roussel M. F., Look A. T., Stanley E. R. The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell. 1985 Jul;41(3):665–676. doi: 10.1016/s0092-8674(85)80047-7. [DOI] [PubMed] [Google Scholar]
  21. Small D., Levenstein M., Kim E., Carow C., Amin S., Rockwell P., Witte L., Burrow C., Ratajczak M. Z., Gewirtz A. M. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):459–463. doi: 10.1073/pnas.91.2.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Spangrude G. J., Heimfeld S., Weissman I. L. Purification and characterization of mouse hematopoietic stem cells. Science. 1988 Jul 1;241(4861):58–62. doi: 10.1126/science.2898810. [DOI] [PubMed] [Google Scholar]
  23. Spangrude G. J., Scollay R. A simplified method for enrichment of mouse hematopoietic stem cells. Exp Hematol. 1990 Sep;18(8):920–926. [PubMed] [Google Scholar]
  24. Springer T., Galfré G., Secher D. S., Milstein C. Mac-1: a macrophage differentiation antigen identified by monoclonal antibody. Eur J Immunol. 1979 Apr;9(4):301–306. doi: 10.1002/eji.1830090410. [DOI] [PubMed] [Google Scholar]
  25. Tsuji K., Zsebo K. M., Ogawa M. Enhancement of murine blast cell colony formation in culture by recombinant rat stem cell factor, ligand for c-kit. Blood. 1991 Sep 1;78(5):1223–1229. [PubMed] [Google Scholar]
  26. Williams D. E., Eisenman J., Baird A., Rauch C., Van Ness K., March C. J., Park L. S., Martin U., Mochizuki D. Y., Boswell H. S. Identification of a ligand for the c-kit proto-oncogene. Cell. 1990 Oct 5;63(1):167–174. doi: 10.1016/0092-8674(90)90297-r. [DOI] [PubMed] [Google Scholar]
  27. Williams N., Bertoncello I., Kavnoudias H., Zsebo K., McNiece I. Recombinant rat stem cell factor stimulates the amplification and differentiation of fractionated mouse stem cell populations. Blood. 1992 Jan 1;79(1):58–64. [PubMed] [Google Scholar]
  28. Zsebo K. M., Wypych J., McNiece I. K., Lu H. S., Smith K. A., Karkare S. B., Sachdev R. K., Yuschenkoff V. N., Birkett N. C., Williams L. R. Identification, purification, and biological characterization of hematopoietic stem cell factor from buffalo rat liver--conditioned medium. Cell. 1990 Oct 5;63(1):195–201. doi: 10.1016/0092-8674(90)90300-4. [DOI] [PubMed] [Google Scholar]
  29. de Vries P., Brasel K. A., Eisenman J. R., Alpert A. R., Williams D. E. The effect of recombinant mast cell growth factor on purified murine hematopoietic stem cells. J Exp Med. 1991 May 1;173(5):1205–1211. doi: 10.1084/jem.173.5.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]

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