Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type i interferon-dependent exhaustion

Taku Sato, Nobuyuki Onai, Hiroki Yoshihara, Fumio Arai, Toshio Suda, Toshiaki Ohteki

Research output: Contribution to journalArticle

234 Citations (Scopus)

Abstract

Type I interferons (IFNs), a family of cytokines, orchestrate numerous biological and cellular processes. Although it is well known that type I IFNs are essential for establishing the host antiviral state, their role in hematopoietic homeostasis has not been studied. Here we show that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs) and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type I IFN signaling, preserves the self-renewal and multilineage differentiation capacity of HSCs. HSCs were substantially less abundant in the bone marrow of Irf2 / as compared to Irf2 +/ mice. Irf2 / HSCs showed enhanced cell cycling status and failed to produce hematopoietic cells in competitive repopulation assays, and the reconstituting capacity of Irf2 / HSCs was restored by disabling type I IFN signaling in these cells. In wild-type mice, injection of poly(I:C), an inducer of type I IFN signaling, or IFN-α induced HSC proliferation, and chronic type I IFN signaling further reduced the number of quiescent HSCs. Notably, combined poly(I:C) and 5-fluorouracil (5-FU) treatment allowed exogenous HSC engraftment and hematopoietic reconstitution in WT mice. Our findings provide insight into the molecular basis for the maintenance of HSC quiescence and may lead to improvements in bone marrow transplantation and type I IFN-based therapies for viral infection and cancer.

Original languageEnglish
Pages (from-to)696-700
Number of pages5
JournalNature Medicine
Volume15
Issue number6
DOIs
Publication statusPublished - 2009 Jun 8

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Interferon Regulatory Factor-2
Interferon Type I
Hematopoietic Stem Cells
Stem cells
Interferons
Poly I-C
Bone
Biological Phenomena
Cell proliferation
Virus Diseases
Bone Marrow Transplantation
Fluorouracil
Antiviral Agents
Assays
Homeostasis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type i interferon-dependent exhaustion. / Sato, Taku; Onai, Nobuyuki; Yoshihara, Hiroki; Arai, Fumio; Suda, Toshio; Ohteki, Toshiaki.

In: Nature Medicine, Vol. 15, No. 6, 08.06.2009, p. 696-700.

Research output: Contribution to journalArticle

Sato, Taku ; Onai, Nobuyuki ; Yoshihara, Hiroki ; Arai, Fumio ; Suda, Toshio ; Ohteki, Toshiaki. / Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type i interferon-dependent exhaustion. In: Nature Medicine. 2009 ; Vol. 15, No. 6. pp. 696-700.
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