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Blood, 15 January 2007, Vol. 109, No. 2, pp. 507-515.
Prepublished online as a Blood First Edition Paper on September 14, 2006; DOI 10.1182/blood-2006-05-025601.
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Submitted May 30, 2006
Accepted September 4, 2006
Regulation of dendritic cell differentiation by bone marrow stroma via different Notch ligands
Pingyan Cheng, Yulia Nefedova, Cesar A. Corzo, and Dmitry I. Gabrilovich*
H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
* Corresponding author; email: dgabril{at}moffitt.usf.edu.
Notch is a major factor mediating interaction between hematopoietic progenitor cells (HPC) and bone marrow stroma (BMS). However its contribution to DC differentiation is controversial. We found that main Notch ligands Delta-1 and Jagged-1 had opposite effect on DC differentiation. Delta-1 promoted generation of fully differentiated DCs, whereas Jagged-1 stimulated accumulation of DC precursors but prevented their transition to terminally differentiated DCs. BMS expressed substantially higher level of Jagged-1 than Delta-1. Just opposite expression pattern was observed in spleen stroma (SS). BMS effect on DC differentiation was similar to that of Jagged-1, whereas effect of SS was similar to the effect of Delta-1. Down-regulation of Jagged-1 in BMS substantially increased DC differentiation. Experiments in vivo with adoptive transfer of DC precursors further supported different role of BMS and SS in DC development. Jagged-1 and Delta-1 equally activated CBF-1/RBPJ transcription factor, which is a major Notch target. However, they produced different pattern of activation of Notch target gene Hes-1. Overexpression of Hes-1 resulted in increased DC differentiation from HPC. Thus, this study not only revealed different role of Notch ligands in DC differentiation but also may provide a new insight into regulation of DC differentiation by BMS.
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