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Blood, 1 August 2008, Vol. 112, No. 3, pp. 560-567.
Prepublished online as a Blood First Edition Paper on May 27, 2008May 23, 2008; DOI 10.1182/blood-2007-10-117820.
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Submitted October 11, 2007
Accepted April 30, 2008
Steel factor coordinately regulates the molecular signature and biologic function of hematopoietic stem cells
David G Kent, Brad J Dykstra, Jay Cheyne, Elaine Ma, and Connie Eaves*
Terry Fox Lab, BC Cancer Agency, Vancouver, BC, Canada
Department of Medical Genetics, Medicine, and Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
* Corresponding author; email: ceaves{at}bccrc.ca.
Hematopoietic stem cells (HSCs) regenerated in vivo display sustained differences in their self-renewal and differentiation activities. Variations in Steel factor (SF) signaling are known to affect these functions in vitro but the cellular and molecular mechanisms involved are not understood. To address these issues, we evaluated highly purified HSCs maintained in single-cell serum-free cultures containing, 20 ng/mL IL-11 plus 1, 10 or 300 ng/mL SF. Under all conditions, >99% of the cells traversed a first cell cycle with similar kinetics. After 8 hours in the 10 or 300 ng/mL SF conditions, the frequency of HSCs remained unchanged. However, in the next 8 hours, i.e., 6 hours before any cell divided, HSC integrity was sustained only in the 300 ng/mL SF cultures. Interestingly, the cells in these cultures also contained significantly higher levels of Bmi1, Lnk and Ezh2 transcripts, but not of several other regulators. Assessment of 21 first division progeny pairs further showed that only those generated in 300 ng/mL SF cultures contained HSCs and pairs of progeny with similar differentiation programs were not observed. Thus, SF signaling intensity can directly and coordinately alter the transcription factor profile and longterm repopulating ability of quiescent HSCs prior to their first division.
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