Cell-cell signaling through NOTCH regulates human embryonic stem cell proliferation

Stem Cells. 2008 Mar;26(3):715-23. doi: 10.1634/stemcells.2007-0368. Epub 2007 Nov 29.


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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • Antigens, Surface / metabolism
  • Apoptosis / drug effects
  • Carcinoma, Embryonal / metabolism
  • Carcinoma, Embryonal / pathology
  • Cell Communication* / drug effects
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mice
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / drug effects
  • Pluripotent Stem Cells / metabolism
  • Protein Processing, Post-Translational / drug effects
  • Protein Structure, Tertiary
  • Protein Transport / drug effects
  • Receptors, Notch / chemistry
  • Receptors, Notch / metabolism*
  • Signal Transduction* / drug effects


  • Antibodies, Monoclonal
  • Antigens, Surface
  • Enzyme Inhibitors
  • Receptors, Notch