IFNα activates dormant haematopoietic stem cells in vivo

MAG Essers, S Offner, WE Blanco-Bose, Z Waibler… - Nature, 2009 - nature.com
MAG Essers, S Offner, WE Blanco-Bose, Z Waibler, U Kalinke, MA Duchosal, A Trumpp
Nature, 2009nature.com
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 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-α (IFNα), HSCs efficiently exit G0 and enter an active cell
cycle. HSCs respond to IFNα treatment by the increased phosphorylation of STAT1 and …
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 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-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), STAT1 (ref. ) or Sca-1 (ref. ) 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-uracil,, 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 cells,, and raise the possibility for new applications of type I interferons to target cancer stem cells.
nature.com