“It may be that, some ages hence... the restoration of grey hairs to juvenility and the renewing of the exhausted marrow may at length be elicited without a miracle”
Joseph Glanvill,
1661AD
Cell-Cell Signaling through NOTCH Regulates Human Embryonic Stem Cell Proliferation.
Stem Cells. 2007 Nov 29 [Epub ahead of print]
Fox V, Gokhale PJ, Walsh JR, Matin M, Jones M, Andrews PW. Centre for Stem Cell Biology, Department of Biomedical Science, University of Sheffield
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.