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

Il-Hoan Oh1, Connie J Eaves

  • 1Terry Fox Laboratory, British Columbia Cancer Agency and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V5Z 1L3 Canada.

Oncogene
|July 9, 2002
PubMed

Insights

Signal transducer and activator of transcription 3 (STAT3) is crucial for hematopoietic stem cell (HSC) self-renewal. Inhibiting STAT3 in HSCs significantly impairs their long-term reconstituting ability in vivo.

Area of Science:

  • Stem cell biology
  • Molecular signaling pathways
  • Hematopoiesis

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is a downstream mediator of gp130 signaling.
  • gp130 receptor activation is known to promote hematopoietic stem cell (HSC) self-renewal.
  • STAT3 expression is slightly elevated in primitive human and murine bone marrow cell subsets.

Purpose of the Study:

  • To investigate the role of the STAT3 signaling pathway in maintaining hematopoietic stem cell (HSC) activity in vivo.
  • To determine if STAT3 is essential for HSC self-renewal and long-term reconstitution.

Main Methods:

  • Retroviral transduction of primitive murine fetal liver cells with dominant-negative (dn) or wild-type (wt) STAT3 constructs.
  • In vivo transplantation assays to assess lympho-myeloid reconstituting ability of transduced HSCs.
  • Colony-forming unit-spleen (CFU-S) and colony-forming cell (CFC) assays to evaluate short-term proliferation potential.

Main Results:

  • Dominant-negative STAT3 transduction markedly and permanently reduced HSCs' in vivo lympho-myeloid reconstituting ability.
  • Short-term proliferation potential (CFU-S and CFC) of HSCs was unaffected by dominant-negative STAT3.
  • Overexpression of wild-type STAT3 had minimal impact on HSCs or progenitor cells.

Conclusions:

  • STAT3 plays a critical, stage-specific, and non-redundant role in maintaining HSC function during division in adult bone marrow.
  • HSCs utilize non-limiting levels of STAT3, which are essential for their long-term self-renewal and reconstitution capacity.

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