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TISSUE-SPECIFIC STEM CELLS

Activation of CCAAT/Enhancer-Binding Protein or PU.1 in Hematopoietic Stem Cells Leads to Their Reduced Self-Renewal and Proliferation

^aCenter of Excellence and
^bDivision of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

Key Words. Hematopoietic stem cell • CCAAT/enhancer-binding protein • PU.1 • Self-renewal

Correspondence: Correspondence: Hideaki Nakajima, M.D., Ph.D., Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Telephone: 81-3-5363-3785; Fax: 81-3-3353-3515; e-mail: hnakajim{at}sc.itc.keio.ac.jp

Received on March 29, 2008; accepted for publication on August 28, 2008.

First published online in STEM CELLS EXPRESS  September 11, 2008.

Previous studies using loss-of-function mutants revealed that CCAAT/enhancer-binding protein (C/EBP) and PU.1 are potential regulators for hematopoietic stem cells (HSCs). To gain further insight into the HSC regulation by C/EBP or PU.1, we used transgenic mice expressing conditional forms of these transcription factors to examine whether their activation alone is sufficient for modulating HSC functions. The activation of C/EBP or PU.1 in HSCs in vitro or in vivo led to their suppression of growth, decreased mixed colony formation, and impaired competitive repopulating activities because of their defective self-renewal. These effects were more prominently observed when C/EBP was activated, and the differentiation capacity to megakaryocytic lineage was selectively impaired upon C/EBP activation. Unexpectedly, the expression of Bmi-1 and HoxB4, well-known regulators for self-renewal of HSCs, was not affected by the activation of C/EBP or PU.1, suggesting that they regulate HSC function through an as yet unknown mechanism. Our data suggest that the activation of C/EBP or PU.1 is sufficient to repress stem cell capacities in HSCs, and their fine-tuned regulation is critical for HSC homeostasis.

Disclosure of potential conflicts of interest is found at the end of this article.