The Notch ligand, Delta-1, inhibits the differentiation of monocytes into macrophages but permits their differentiation into dendritic cells

Notch-mediated cellular interactions are known to regulate cell fate decisi ons In various developmental systems. A previous report Indicated that mono cytes express relatively high amounts of Notch-1 and Notch-2 and that the I mmobilized extracellular domain of the Notch ligand, Delta-1 Delta(ext-myc) ), induces apoptosis in peripheral blood monocytes cultured with macrophage colony-stimulating factor (M-CSF), but not granulocyte-macrophage CSF (GM- CSF). The present study determined the effect of Notch signaling on monocyt e differentiation into macrophages and dendritic cells. Re-suits showed tha t immobilized Deltaext-myc Inhibited differentiation of monocytes into matu re macrophages (CD1a(+/-)CD14(+/-)CD64(+)) with GM-CSF. However, Deltaext-m yc permitted differentiation into immature dendritic cells (CD1a(+)CD14(-)C D64(-)) with GMCSF and interleukin 4 (IL-4), and further differentiation in to mature dendritic cells (CD1a(+)CD83(+)) with GM-CSF, IL-4, and tumor nec rosis factor-alpha (TNF-alpha). Notch signaling affected the differentiatio n of CD1a(-)CD14(+) macrophage/dendritic cell precursors derived in vitro f rom CD34(+) cells. With GM-CSF and TNF-alpha, exposure to Delta(ext-myc) in creased the proportion of precursors that differentiated into CD1a(+)CD14(- ) dendritic cells (51% in the presence of Delta(ext-myc) versus 10% in cont rol cultures), whereas a decreased proportion differentiated into CD1a(-)CD 14(+) macrophages (6% versus 65%). These data Indicate a role for Notch sig naling in regulating cell fate decisions by bipotent macrophage/dendritic p recursors. (C) 2001 by The American Society of Hematology.