Open AccessCell‐Cell Signaling Through NOTCH Regulates Human Embryonic Stem Cell Proliferation
Author(s) -
Fox Victoria,
Gokhale Paul J.,
Walsh James R.,
Matin Maryam,
Jones Mark,
Andrews Peter W.
Publication year - 2008
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1634/stemcells.2007-0368
Subject(s) - notch signaling pathway , biology , microbiology and biotechnology , hes3 signaling axis , embryonic stem cell , notch proteins , cell growth , signal transduction , stem cell , cell , cellular differentiation , induced pluripotent stem cell , genetics , gene
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 γ‐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.