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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2002-05-1602.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 3983-3989
HEMATOPOIESIS
Cell intrinsic defects in cytokine responsiveness of
STAT5-deficient hematopoietic stem cells
Heath L. Bradley,
Teresa S. Hawley, and
Kevin D. Bunting
From the Hematopoiesis Department and the Flow
Cytometry Facility, American Red Cross Holland Laboratory,
Rockville, MD; and the Department of Anatomy and Cell Biology, The
George Washington University, Washington, DC.
Secreted growth factors are integral components of the bone marrow
(BM) niche and can regulate survival, 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 define intracellular cytokine signaling in HSC function, we have analyzed mice lacking expression of
both signal transducer and activator of transcription 5a (STAT5a) and STAT5b (STAT5ab /). These studies
specifically avoided possible autoimmune and/or splenomegaly
disease-mediated indirect effects on HSC function by using 2 independent approaches: (1) by crossing onto the C57Bl/6 RAG2/ background, and (2) by generation of
wild-type chimeric mice reconstituted with transplanted
STAT5ab/ BM cells. These experiments demonstrated that
STAT5-deficient HSCs have cell autonomous defects in competitive
long-term repopulating activity. Furthermore, in the chimeric mice,
injected wild-type BM cells showed a progressive multilineage
competitive repopulating advantage in vivo, demonstrating that
steady-state hematopoiesis was also highly STAT5-dependent. 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
reduced expansion of total nucleated cells was observed in response to
cocktails containing interleukin 3 (IL-3), IL-6, stem cell factor
(SCF), Flt3 ligand, and thrombopoietin. Notably, a 10-fold reduction in
expansion 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 major role for STAT5 activation as a cellular determinant of
cytokine-mediated HSC repopulating potential but not self-renewal capacity.
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