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補上原文的摘要

Nature Medicine 15, 696 - 700 (2009)
Published online: 31 May 2009 | doi:10.1038/nm.1973

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

Taku Sato1,2, Nobuyuki Onai1,2, Hiroki Yoshihara3, Fumio Arai3, Toshio Suda3
& Toshiaki Ohteki1,2,4

Abstract

Type I interferons (IFNs), a family of cytokines, orchestrate numerous
biological and cellular processes1, 2, 3. Although it is well known that type
I IFNs are essential for establishing the host antiviral state4, 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 signaling5, 6, 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-alpha 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.

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1967.6.2 -- 1999.9.16 Ex-USS DD-521 Kimberly 成軍三十二年除役

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