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IFNα activates dormant haematopoietic stem cells in vivo

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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Figure 1: IFNα induces efficient cell cycle entry of dormant HSCs in vivo.
Figure 2: A direct effect on HSCs, combined with an indirect mechanism, promotes HSC proliferation in response to IFNα in vivo.
Figure 3: IFNα-activated HSCs upregulate and are dependent on STAT1 and Sca-1 signalling.
Figure 4: Priming of IFNα followed by 5-FU treatment or chronic IFNα stimulation causes HSC loss.

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Gene Expression Omnibus

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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.

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Correspondence to Andreas Trumpp.

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Essers, M., Offner, S., Blanco-Bose, W. et al. IFNα activates dormant haematopoietic stem cells in vivo. Nature 458, 904–908 (2009). https://doi.org/10.1038/nature07815

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