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First published online November 29, 2007
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2007-0368v1
26/3/715    most recent
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Submitted on May 13, 2007
Accepted on November 19, 2007

EMBRYONIC STEM CELLS

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

V. Fox 1, P. J. Gokhale 2, J. R. Walsh 3, M. Matin 4, M. Jones 2, P. W. Andrews 2*

1 Centre for Stem Cell Biology, Department of Biomedical Science. University of Sheffield, Western Bank, Sheffield, S10 2TN, UK, Present address: Center for Stem Cell and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA
2 Centre for Stem Cell Biology, Department of Biomedical Science. University of Sheffield, Western Bank, Sheffield, S10 2TN, UK
3 Axordia Limited, The Sheffield Bioincubator, 40 LeavyGreave Road, Sheffield, S3 7RD. UK
4 Department of Biology, Institute of Biotechnology and Tissue Engineering, Ferdowsi University of Mashhad, Mashhad, Iran

* To whom correspondence should be addressed. E-mail: P.W.Andrews{at}sheffield.ac.uk.


  Abstract

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. Further, the proliferation of human EC cells, as well as the expression of several downstream NOTCH target genes, was markedly reduced after siRNA knock-down of NOTCH1, NOTCH2 and the canonical effector, CBF-1, or after blocking NOTCH signaling with the gamma-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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V. Fox and P. J. Gokhale contributed equally to this work.

 Key Words. Human, Embryonic Stem Cell, Embryonal Carcinoma, NOTCH, {gamma}-secretase, Apoptosis






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