Notch signaling is necessary but not sufficient for differentiation of dendritic cells.
The Notch family of receptors plays an important role in regulation of cell differentiation via direct contact between hematopoietic progenitor cells (HPCs) and bone marrow stroma (BMS). However the precise contribution of Notch in dendritic cell (DC) differentiation is controversial. In 2 different experimental systems using Notch-1-null embryonic stem cells and Notch-1-deficient HPCs we have found that Notch-1 is necessary for DC differentiation. However, activation of Notch-1 and Notch-2 with cell-bound Notch ligand did not result in differentiation of mature DCs or macrophages. Instead, it caused accumulation of immature myeloid cells. Removal of feeder cells resulted in rapid differentiation of DCs and macrophages. Addition of interleukin 4 (IL-4) into the culture dramatically increased accumulation of functionally potent DCs. Lipopolysaccharide was not able to reproduce this effect. Thus, these data indicate that Notch signaling prevents differentiation of mature myeloid cells. Instead, it results in accumulation of precursors readily able to differentiate into mature DCs once the Notch signal is stopped (eg, after cell emigration from bone marrow) and in the presence of other additional differentiation signals provided by IL-4. Thus, Notch is required but not sufficient for DC differentiation.
Cheng
Pingyan
P
H. Lee Moffitt Cancer Center, University of South Florida, MRC-2E, Rm 2067, 12902 Magnolia Dr, Tampa, FL 33612, USA. dgabril@moffitt.usf.edu
Nefedova
Yulia
Y
Miele
Lucio
L
Osborne
Barbara A
BA
Gabrilovich
Dmitry
D
D000818:Animals; D002454:Cell Differentiation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology*; D005260:Female; D015847:Interleukin-4 / Q000494:pharmacology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000502:physiology; D051880:Receptors, Notch; D015398:Signal Transduction; D017154:Stromal Cells; D014157:Transcription Factors
D008565:Membrane Proteins; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D014157:Transcription Factors; D015847:Interleukin-4