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

Oncogene. 2002 Jul 18;21(31):4778-87. doi: 10.1038/sj.onc.1205592.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line
  • Cells, Cultured
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / physiology*
  • Humans
  • Kinetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Models, Biological
  • Mutation
  • RNA, Messenger / biosynthesis
  • STAT3 Transcription Factor
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Transduction, Genetic

Substances

  • DNA-Binding Proteins
  • RNA, Messenger
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Trans-Activators