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STEM CELL GENETICS AND GENOMICS

HES1 Inhibits Cycling of Hematopoietic Progenitor Cells via DNA Binding

^a Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, and
^b Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;
^c Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

Key Words. HES1 • Notch signaling pathway • Hematopoietic stem cells • Hematopoietic progenitor cells • Stem cell self-renewal • Cell cycle • bHLH

Correspondence: Curt I. Civin, M.D., The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, Room 2M44, 1650 Orleans Street, Baltimore, Maryland 21231, USA. Telephone: 410-955-8816; Fax: 410-955-8897; e-mail: civincu{at}jhmi.edu

Received November 29, 2005; accepted for publication February 24, 2006.
Notch signaling is implicated in stem cell self-renewal, differentiation, and other developmental processes, and the Drosophila hairy and enhancer of split (HES) 1 basic helix-loop-helix protein is a major downstream effector in the Notch pathway. We found that HES1 was expressed at high levels in the hematopoietic stem cell (HSC)–enriched CD34⁺/[CD38/Lin]^{– /low} subpopulation but at low levels in more mature progenitor cell populations. When CD34⁺ cells were cultured for 1 week, the level of HES1 remained high in the CD34⁺ subset that had remained quiescent during ex vivo culture but was reduced in CD34⁺ cells that had divided. To investigate the effects of HES1 in human and mouse hematopoietic stem–progenitor cells (HSPCs), we constructed conditional lentiviral vectors (lentivectors) to introduce transgenes encoding either wild-type HES1 or a mutant lacking the DNA-binding domain (BHES1). We found that lentivector-mediated HES1 expression in CD34⁺ cells inhibited cell cycling in vitro and cell expansion in vivo, associated with upregulation of the cell cycle inhibitor p21^cip1/Waf1 (p21). The HES1 DNA–binding domain was required for these actions. HES1 did not induce programmed cell death or alter differentiation in HSPCs, and while short-term repopulating activity was reduced in HES1-transduced mouse and human cells, long-term reconstituting HSC function was preserved. Our data characterize the complex, cell context–dependent actions of HES1 as a major downstream Notch signaling regulator of HSPC function.

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