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EMBRYONIC STEM CELLS |
aCentre for Stem Cell Biology, Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom;
bAxordia Ltd., Sheffield, United Kingdom;
cDepartment of Biology, Institute of Biotechnology and Tissue Engineering, Ferdowsi University of Mashhad, Mashhad, Iran
Key Words. Human • Embryonic stem cell • Embryonal carcinoma • NOTCH • 
-Secretase • Apoptosis
Correspondence: P.W. Andrews, B.Sc. (Hons), D.Phil., Centre for Stem Cell Biology, Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom. Telephone: 44-(0)114-222-4173; Fax: 44-(0)114-222-2399; e-mail: P.W.Andrews{at}sheffield.ac.uk
Received May 13, 2007;
accepted for publication November 19, 2007.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLS EXPRESS November 29, 2007.
Unlike pluripotent mouse embryonic stem (ES) cells, human ES cells and their malignant equivalents, embryonal carcinoma (EC) cells, require close cell-cell contact for efficient growth. Signaling through the NOTCH receptor, initiated by interaction with ligands of the DELTA/JAGGED family expressed on neighboring cells, plays a role in regulating the self-renewal of several stem cell systems. Members of the NOTCH and DELTA/JAGGED families are expressed by human EC and ES cells, and we have therefore investigated the possible role of NOTCH in the maintenance of these cells. Cleavage of both NOTCH1 and NOTCH2 to yield the intracellular domain responsible for the canonical signaling pathway of NOTCH was detected in several human EC and ES cell lines, suggesting that NOTCH signaling is active. Furthermore, the proliferation of human EC cells, as well as the expression of several downstream NOTCH target genes, was markedly reduced after small interfering RNA knockdown of NOTCH1, NOTCH2, and the canonical effector CBF-1 or after blocking NOTCH signaling with the -secretase inhibitor L-685,458. The inhibitor also caused a reduction in the growth of human ES cells, although without evidence of differentiation. The results indicate that cell-cell signaling through the NOTCH system provides a critical cue for the proliferation of human EC and ES cell in vitro.
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