Journal
STEM CELLS
Volume 24, Issue 4, Pages 876-888Publisher
ALPHAMED PRESS
DOI: 10.1634/stemcells.2005-0598
Keywords
HES1; Notch signaling pathway; hematopoietic stem cells; hematopoietic progenitor cells; stem cell self-renewal; cell cycle; bHLH
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Funding
- NCI NIH HHS [CA070970] Funding Source: Medline
- NHLBI NIH HHS [HL073781, HL072229] Funding Source: Medline
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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 (Delta 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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