Skip to main content
SpringerLink
Log in

Effects of Leukemia Inhibitory Factor (LIF) on Gene Transfer Efficiency into Murine Hematolymphoid Progenitors

  • Chapter
Mechanisms of Lymphocyte Activation and Immune Regulation III

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 292))

Abstract

We have investigated the effects of the cytokine leukemia inhibitory factor (LIF) on recovery and retroviral infection of murine hematopoietic stem cells maintained in short-term culture. Up to a two-fold increase in CFU-S13 recovery was observed, from 9.7 x 10-5 cells in untreated controls to 17.6 x 10-5 cells when lOU/ml LIF is added to the culture medium. Intermediate concentrations of LIF (.lU/ml and lU/ml) were not significantly different from the control. Histological analysis of spleen colonies harvested thirteen days posttransplant demonstrated that LIF does not cause a detectable alteration in the differentiative potential of CFU-S13. The efficiency of retroviral-vector infection in CFU-S13 is also improved, from 15% (24/158) in untreated controls to 91% (116/127) at a LIF concentration of l0U/ml. LIF concentrations of .lU/ml and lU/ml increased infection efficiency to 35% (14/40) and 71% (37/51), respectively. Analysis of proviral insertion sites in spleen colonies indicated that some CFU-S13 precursors were infected in the LIF-treated marrows, but no identical pairs were detected in the controls. Finally, long-term expression of provirally-encoded human adenosine deaminase (hADA) was measured in hematopoietic tissues of bone marrow transplant recipients six months posttransplant. In all tissues analyzed (spleen, thymus, bone marrow, splenic B cells, peritoneal macrophages, and blood) differentiated progeny of LIF-treated marrows had higher levels of hADA than untreated controls. Tenfold increases in levels of hADA are detected in some tissues, but levels were variable. These experiments demonstrate that LIF directly or indirectly enhances retroviral infection efficiency of hematopoietic stem cells, and might be used to improved existing gene transfer protocols.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 16.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. J. W. Belmont, G. R. MacGregor, K. Wager-Smith, F. A. Fletcher, K. A. Moore, D. Hawkins, D. Villalon, S. M.-W. Chang, and C. T. Caskey, Expression of human adenosine deaminase in murine hematopoietic cells, Mol. Cell Biol. 8:5116 (1988).

    PubMed  CAS  Google Scholar 

  2. K. A. Moore, F. A. Fletcher, D. K. Villalon, A. E. Utter, and J. W. Belmont, Human adenosine deaminase expression in mice, Blood 75:2085 (1990).

    PubMed  CAS  Google Scholar 

  3. L. G. Lajtha, Stem cell concepts, Differentiation 14:23 (1979).

    Article  PubMed  CAS  Google Scholar 

  4. D. M. Bodine, S. Karlsson, and A. W. Nienhuis, Combination of interleukins 3 and 6 preserves stem cell function in culture and enhances retrovirus-mediated gene transfer into hematopoietic stem cells, Proc. Natl. Acad. Sci. USA 86:8897 (1989).

    Article  PubMed  CAS  Google Scholar 

  5. D. J. Hilton, N. A. Nicola, N. M. Gough, and D. Metcalf, Resolution and purification of three distinct factors produced by Krebs ascites cells which have differentiation-including activity on murine myeloid leukemic cell lines, J. Biol. Chem 263:9238 (1988).

    PubMed  CAS  Google Scholar 

  6. D. Metcalf, Actions and interactions of G-CSF, LIF, and IL-6 on normal and leukemic murine cells, Leukemia 3:349 (1989).

    PubMed  CAS  Google Scholar 

  7. A. Godard, H. Gascan, J. Naulet, M.-A. Peyrat, Y. Jacques, J.-P. Soulillou, and J.-F. Moreau, Biochemical characterization and purification of HILDA, a human lymphokine active on eosinophils and bone marrow cells, Blood 71:1618 (1988).

    PubMed  CAS  Google Scholar 

  8. D. J. Hilton, N. A. Nicola, and D. Metcalf, Specific binding of murine leukemia inhibitory factor to normal and leukemic monocytic cells, Proc. Natl. Acad. Sci. USA 85:5971 (1988).

    Article  PubMed  CAS  Google Scholar 

  9. A. G. Smith, J. K. Heath, D. D. Donaldson, G. G. Wong, J. Moreau, M. Stahl, and D. Rogers, Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides, Nature 336:688 (1988).

    Article  PubMed  CAS  Google Scholar 

  10. R. L. Williams, D. J. Hilton, S. Pease, T. A. Willson, C. L. Stewart, D. P. Gearing, E. F. Wagner, D. Metcalf, N. A. Nicola, and N. M. Gough, Myeloid leukemia inhibitory factor maintains the developmental potential of embryonic stem cells, Nature 336:684 (1988).

    Article  PubMed  CAS  Google Scholar 

  11. S. C. Kogan, M. Doherty, and J. Gitschier, An improved method for prenatal diagnosis of genetic diseases by amplified DNA sequences, N. Engl. J. Med 317:985 (1987).

    Article  PubMed  CAS  Google Scholar 

  12. E. M. Southern, Detection of specific sequences among DNA fragments separated by gel electrophoresis, J. Mol. Biol. 98:503 (1975).

    Article  PubMed  CAS  Google Scholar 

  13. G. S. Adrian, D. A. Wiginton, and J. J. Hutton, Structure of adenosine deaminase mrnas from normal and adenosine deaminase deficient human cell lines, Mol. Cell. Biol. 4:1712 (1984).

    PubMed  CAS  Google Scholar 

  14. D. Metcalf, T. Maekawa, D. Hilton, N. Nicola, D. Gearing, and N. Gough, Interactions of leukemia inhibitory factor (LIF) IL-6 and colony-stimulating factors on murine and human leukemic cells. Exp. Hematol. 17:483 (1989).

    Google Scholar 

  15. J. Harel, E. Rassart, and P. Jolicoeur, Cell cycle dependence of synthesis of unintegrated viral DNA in mouse cells newly infected with muine leukemia virus, Virology 110:202 (1981).

    Article  PubMed  CAS  Google Scholar 

  16. I. S. Y. Chen, and H. Temin, Establishment of infection by spleen necrosis virus: inhibition in stationary cells and the role of secondary infection, J, Virol. 41:183 (1982).

    CAS  Google Scholar 

  17. D. E. Williams, A. E. Namen, D. Y. Mochizuki, and R. W. Overell, Clonal growth of murine pre-B colony forming cells and their targeted infection by a retroviral vector: dependence on interleukin-7, Blood 75:1132 (1990),

    PubMed  CAS  Google Scholar 

  18. G. M. Springett, R. C. Moen, S. Anderson, R. M. Blaese, and W. F. Anderson, Infection efficiency of T lymphocytes with amphotropic retroviral vectors is cell cycle dependent, J. Virol 63:3865 (1989).

    PubMed  CAS  Google Scholar 

  19. A. J. Becker, E. A. Mc-Culloch, L. Siminovitch, and J. E. Till, The effect of different demands for blood cell production on DNA synthesis by haemopoietic colony forming cells of mice, Blood 26:296 (1965).

    PubMed  CAS  Google Scholar 

  20. B. I. Lord, L. G. Lajtha, and J. Gidali, Measurement of the kinetic status of bone marrow precursor cells: three cautionary tales, Cell and Tissue Kin 7:507 (1974).

    CAS  Google Scholar 

  21. A. G. Leary, G. C. Wong, S. C. Clark, and M. Ogawa, Leukemia inhibitory factor (LIF)/differentiation-inducing activity (DIA) is a synergistic factor for human hemopoietic stem cells, Exp. Hematol. 17:524 (1989).

    Google Scholar 

  22. J. Ikebuchi, G. G. Wong, S. C. Clark, J. N. Ihle, Y. Hirai, and M. Ogawa, Interleukin 6 enhancement of interleukin 3-dependent proliferation of multi-potential hemopoietic progenitors, Proc. Natl. Acad. Sci. USA 84:9035 (1987).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute, USA

    John W. Belmont

  2. Institute for Molecular Genetics, Baylor College of Medicine, Houston, Texas, USA

    Frederick A. Fletcher, Kateri A. Moore & John W. Belmont

  3. Immunex Research and Development Corporation, Seattle, Washington, USA

    Douglas E. Williams, Dirk Anderson & Charles Maliszewski

Authors
  1. Frederick A. Fletcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kateri A. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Douglas E. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dirk Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Charles Maliszewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John W. Belmont
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Medicine, University of California, Irvine, California, 92717, USA

    Sudhir Gupta

  2. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA

    William E. Paul

  3. The Howard Hughes Medical Institute, University of Alabama, Birmingham, Alabama, 35294, USA

    Max D. Cooper

  4. Department of Biology, California Institute of Technology, Pasadena, California, 91125, USA

    Ellen V. Rothenberg

Rights and permissions

Reprints and permissions

Copyright information

© 1991 Plenum Press, New York

About this chapter

Cite this chapter

Fletcher, F.A., Moore, K.A., Williams, D.E., Anderson, D., Maliszewski, C., Belmont, J.W. (1991). Effects of Leukemia Inhibitory Factor (LIF) on Gene Transfer Efficiency into Murine Hematolymphoid Progenitors. In: Gupta, S., Paul, W.E., Cooper, M.D., Rothenberg, E.V. (eds) Mechanisms of Lymphocyte Activation and Immune Regulation III. Advances in Experimental Medicine and Biology, vol 292. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5943-2_15

Download citation

  • DOI: https://doi.org/10.1007/978-1-4684-5943-2_15

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4684-5945-6

  • Online ISBN: 978-1-4684-5943-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation