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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2007-0368v1 26/3/715    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Google Scholar Articles by Fox, V. Articles by Andrews, P. W. PubMed PubMed Citation Articles by Fox, V. Articles by Andrews, P. W.

EMBRYONIC STEM CELLS

Cell-Cell Signaling Through NOTCH Regulates Human Embryonic Stem Cell Proliferation

^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.
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.

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