Overexpression of a dominant negative form of STAT3 selectively impairs hematopoietic stem cell activity

被引:52
作者
Oh, IH
Eaves, CJ
机构
[1] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada
[2] Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 1L3, Canada
关键词
dominant negative STAT3; stem cells; hematopoiesis; gp-130; self-renewal;
D O I
10.1038/sj.onc.1205592
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
STAT3 is a key downstream signaling intermediate of gp130, a receptor previously shown to activate hematopoietic stem cell (HSC) self-renewal divisions. These findings prompted us to investigate if the STAT3 pathway is important to HSC activity in vivo. Initial semi-quantitative RT-PCR analyses showed STAT3 to be expressed at slightly higher levels in primitive subsets of both human and murine adult bone marrow cells. To test the effect of abrogating STAT3 activity in HSCs, primitive murine fetal liver cells were transduced at high efficiency with either a bicistronic dominant-negative (dn) or wild-type (wt) STAT3-IRES-GFP retrovirus. Dn STAT3-transduced HSCs showed markedly and permanently reduced in vivo lympho-myeloid reconstituting ability relative to co-transplanted non-transduced HSCs or HSCs transduced with a control (GFP-only) vector. In contrast, the activity of dn STAT3-transduced cells with short term in vivo (CFU-S) or in vitro (CFC) proliferation potential was not affected. Overexpression of wt-STAT3 had very little effect on either HSCs or shorter term progenitors. These findings suggest HSCs express non-limiting levels of STAT3 which, nevertheless, play an important stage-specific and non-redundant role in maintaining the function of HSCs stimulated to divide in adult marrow tissue.
引用
收藏
页码:4778 / 4787
页数:10
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