IFNa activates dormant HSCs in vivo

Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. Upon injury these cells are induced to proliferate in order to quickly re-establish homeostasis. 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-alpha (IFN), HSCs efficiently exit G0 and enter an active cell cycle. HSCs respond to IFN treatment by increased phosphorylation of STAT1 and PKB/Akt, expression of IFN target genes and up-regulation of stem cell antigen-1 (Sca-1). HSCs lacking either the interferon-/ receptor (IFNAR), STAT1 or Sca-1 are insensitive to IFN stimulation, demonstrating that STAT1 and Sca-1 mediate IFN induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-FU1, HSCs pre-treated (primed) with IFN and thus induced to proliferate are efficiently eliminated by 5-FU exposure in vivo. Conversely, HSCs chronically activated by IFN are functionally compromised and are rapidly out competed by non-activatable IFNAR-/- cells in competitive repopulation assays. In summary, while chronic activation of the IFN pathway in HSCs impairs their function, acute IFN treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFN on leukemic cells and raise the possibility for novel applications of type I interferons to target cancer stem cells.

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