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Prepublished online as a Blood First Edition Paper on August 1, 2002July 25, 2002; DOI 10.1182/blood-2002-05-1602.
Submitted May 31, 2002
Accepted July 3, 2002
Cell Intrinsic Defects in Cytokine Responsiveness of STAT5-Deficient Hematopoietic Stem Cells
Heath L Bradley, Teresa S Hawley, and Kevin D Bunting*
Hematopoiesis Department, American Red Cross Holland Laboratory, Rockville, MD, USA
Hematopoiesis Department, American Red Cross Holland Laboratory, Rockville, MD, USA; Flow Cytometry Facility, American Red Cross Holland Laboratory, Rockville, MD, USA
Hematopoiesis Department, American Red Cross Holland Laboratory, Rockville, MD, USA; Anatomy and Cell Biology Department, The George Washington University, Washington, DC, USA; Anatomy and Cell Biology Department, The George Washington University, Washington, DC, USA
* Corresponding author; email: buntingk{at}usa.redcross.org.
Secreted growth factors are integral components of the bone marrow (BM) niche and can regulate proliferation and differentiation of committed hematopoietic stem cells (HSCs). However, downstream genes activated in HSCs by early acting cytokines are not well characterized. To better understand intracellular cytokine signaling in HSC function, we have analyzed mice lacking expression of both STAT5a and STAT5b (STAT5ab-/-). We avoided possible autoimmune and/or splenomegaly disease cell non-autonomous effects by two independent approaches; 1) crossing onto the C57Bl/6 RAG2-/- background and 2) generation of wild-type transplanted chimeric mice reconstituted with STAT5ab-/- BM cells. The experiments demonstrated that STAT5-deficient HSCs have cell intrinsic defects in competitive long-term repopulating activity. Furthermore, in the chimeric mice, injected wild-type BM cells showed a strong multilineage competitive repopulating advantage in vivo, similar to that previously described in stem cell factor (SCF)/c-kit signaling defective W/Wv mice. Consistent with the in vivo repopulating deficiency, when Sca-1+c-kit+lin- (KLS) cells were isolated and stimulated with growth factors in vitro, up to a 13-fold reduction in proliferation was observed in response to cocktails containing IL-3, IL-6, SCF, Flt3 ligand, and thrombopoietin. A 10-fold reduction in proliferation was observed with IL-3 and SCF. However, STAT5 activation was not required for regeneration of the KLS pool in vivo following transplant or for secondary repopulating ability. These studies support a role for STAT5 activation downstream of SCF/c-kit as a cellular determinant of HSC proliferation and differentiation but not self-renewal.
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