Letter | Published:

IFNα activates dormant haematopoietic stem cells in vivo

Nature volume 458, pages 904908 (16 April 2009) | Download Citation

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Abstract

Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. After injury these cells are induced to proliferate to quickly re-establish homeostasis1. The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-α (IFNα), HSCs efficiently exit G0 and enter an active cell cycle. HSCs respond to IFNα treatment by the increased phosphorylation of STAT1 and PKB/Akt (also known as AKT1), the expression of IFNα target genes, and the upregulation of stem cell antigen-1 (Sca-1, also known as LY6A). HSCs lacking the IFNα/β receptor (IFNAR)2, STAT1 (ref. 3) or Sca-1 (ref. 4) are insensitive to IFNα stimulation, demonstrating that STAT1 and Sca-1 mediate IFNα-induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-fluoro-uracil1,5, HSCs pre-treated (primed) with IFNα and thus induced to proliferate are efficiently eliminated by 5-fluoro-uracil exposure in vivo. Conversely, HSCs chronically activated by IFNα are functionally compromised and are rapidly out-competed by non-activatable Ifnar-/- cells in competitive repopulation assays. Whereas chronic activation of the IFNα pathway in HSCs impairs their function, acute IFNα treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNα on leukaemic cells6,7, and raise the possibility for new applications of type I interferons to target cancer stem cells8.

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Gene Expression Omnibus

Data deposits

The microarray data have been deposited in the NCBI Gene Expression Omnibus (GEO) and are accessible through GEO series accession number GSE14361.

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Acknowledgements

We are grateful to M. Aguet for discussions and advice throughout the project, and for providing mouse strains. We thank D. Tough for providing mouse recombinant IFNα4, T. Pedrazzini, W. Stanford and M. Müller for mouse strains, K. Harshman and O. Hagenbüchle and the DAFL team for excellent service and help with the DNA microarrays. We thank C. Dubey and D. Aubry for animal husbandry, genetic screening and technical help, and J. Roberts for FACS sorting. We are grateful to A. Wilson for comments on the manuscript. M.A.G.E. is the recipient of an EMBO long-term fellowship. This work was supported by grants to A.T. from the Swiss National Science Foundation, the Swiss Cancer League, the EU- FP6 Program ‘INTACT’, the EU-FP7 Program ‘EuroSyStem’ and to UK from the Deutsche Forschungsgemeinschaft (SFB432.B15).

Author Contributions A.T., M.A.G.E. and U.K. designed the experiments and analysed the data. M.A.G.E., S.O. and Z.W. performed the experiments. W.E.B.-B. carried out the microarray analysis. A.T., M.A.G.E. and M.D. wrote the paper.

Author information

Affiliations

  1. Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany

    • Marieke A. G. Essers
    •  & Andreas Trumpp
  2. Heidelberg Institute for Stem Cell Technologies and Experimental Medicine (HI-STEM), Im Neuenheimer Feld 280. D-69120 Heidelberg, Germany

    • Marieke A. G. Essers
    •  & Andreas Trumpp
  3. Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC—Swiss Institute for Experimental Cancer Research, School of Life Science, 1015 Lausanne, Switzerland

    • Sandra Offner
    • , William E. Blanco-Bose
    •  & Andreas Trumpp
  4. Division of Immunology, Paul Ehrlich Institute, D-63225 Langen, Germany

    • Zoe Waibler
    •  & Ulrich Kalinke
  5. TWINCORE—Centre for Experimental and Clinical Infection Research Feodor-Lynen-Str. 7, 30625 Hannover, Germany

    • Ulrich Kalinke
  6. Service and Central Laboratory of Hematology, CHUV, University Hospitals of Lausanne, CH-1011 Lausanne, Switzerland

    • Michel A. Duchosal

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Corresponding author

Correspondence to Andreas Trumpp.

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    Supplementary Information

    This file contains Supplementary Methods, Supplementary References, Supplementary Figures 1-4 with Legends and Supplementary Table 1

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https://doi.org/10.1038/nature07815

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