IFNalpha activates dormant haematopoietic stem cells in vivo.

Détails

ID Serval
serval:BIB_8188D93E49A4
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
IFNalpha activates dormant haematopoietic stem cells in vivo.
Périodique
Nature
Auteur(s)
Essers M.A., Offner S., Blanco-Bose W.E., Waibler Z., Kalinke U., Duchosal M.A., Trumpp A.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Statut éditorial
Publié
Date de publication
2009
Peer-reviewed
Oui
Volume
458
Numéro
7240
Pages
904-908
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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-alpha (IFNalpha), HSCs efficiently exit G(0) and enter an active cell cycle. HSCs respond to IFNalpha treatment by the increased phosphorylation of STAT1 and PKB/Akt (also known as AKT1), the expression of IFNalpha target genes, and the upregulation of stem cell antigen-1 (Sca-1, also known as LY6A). HSCs lacking the IFNalpha/beta receptor (IFNAR), STAT1 (ref. 3) or Sca-1 (ref. 4) are insensitive to IFNalpha stimulation, demonstrating that STAT1 and Sca-1 mediate IFNalpha-induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-fluoro-uracil, HSCs pre-treated (primed) with IFNalpha and thus induced to proliferate are efficiently eliminated by 5-fluoro-uracil exposure in vivo. Conversely, HSCs chronically activated by IFNalpha are functionally compromised and are rapidly out-competed by non-activatable Ifnar(-/-) cells in competitive repopulation assays. Whereas chronic activation of the IFNalpha pathway in HSCs impairs their function, acute IFNalpha treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNalpha on leukaemic cells, and raise the possibility for new applications of type I interferons to target cancer stem cells.
Mots-clé
Animals, Antigens, Ly/metabolism, Cell Count, Cell Cycle/drug effects, Cell Proliferation/drug effects, Fluorouracil/pharmacology, Hematopoietic Stem Cells/cytology, Hematopoietic Stem Cells/drug effects, Interferon-alpha/pharmacology, Membrane Proteins/deficiency, Membrane Proteins/metabolism, Mice, Mice, Inbred C57BL, Phosphorylation/drug effects, Receptor, Interferon alpha-beta/deficiency, Receptor, Interferon alpha-beta/metabolism, STAT1 Transcription Factor/deficiency, STAT1 Transcription Factor/metabolism, Signal Transduction/drug effects, Up-Regulation/drug effects
Pubmed
Web of science
Création de la notice
10/02/2010 15:26
Dernière modification de la notice
03/03/2018 18:48
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