Regulation of dendritic-cell differentiation by bone marrow stroma via different Notch ligands
Regulation of dendritic-cell differentiation by bone marrow stroma via different Notch ligands
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DOI：
10.1182/blood-2006-05-025601
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发表时间：
2007-01-15
期刊：
影响因子：
20.3
通讯作者：
Gabrilovich, Dmitry I.
中科院分区：
文献类型：
--
作者：
Cheng, Pingyan;Nefedova, Yulia;Gabrilovich, Dmitry I.
Notch是调节造血祖细胞和骨髓基质相互作用的主要因素。然而，其在树突状细胞(DC)分化中的作用仍存在争议。我们发现主要的Notch配体Delta-1和Jagge-1对DC的分化有相反的作用。Delta-1促进完全分化的DC的产生，而Jagge-1刺激DC前体的积累，但阻止其向终末分化的DC的转化。BMS表达的锯齿状蛋白-1显著高于Delta-1。而在脾间质(SS)中的表达模式正好相反。BMS对DC分化的影响与Jagge-1相似，而SS的作用与Delta-1相似。BMS中Jagge-1的下调显著增加了DC的分化。体内过继转移DC前体的实验进一步支持了BMS和SS在DC发育中的不同作用。Jagge-1和Delta-1同样激活CBF-1/RBPJ kappa转录因子，这是Notch的主要靶标。然而，他们产生了不同的Notch靶基因Hes1的激活模式。Hes1过表达导致DC向HPC分化的增加。因此，本研究不仅揭示了Notch配体在DC分化中的不同作用，而且可能为BMS对DC分化的调控提供新的视角。
Notch is a major factor mediating interaction between hematopoietic progenitor cells (HPCs) and bone marrow stroma (BMS). However its contribution to dendritic cell (DC) differentiation is controversial. We found that main Notch ligands Delta-1 and Jagged-1 had the 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 a substantially higher level of Jagged-1 than Delta-1. Just the opposite expression pattern was observed in spleen stroma (SS). The BMS effect on DC differentiation was similar to that of Jagged-1, whereas the effect of SS was similar to the effect of Delta-1. Downregulation of Jagged-1 in BMS substantially increased DC differentiation. Experiments in vivo with adoptive transfer of DC precursors further supported the different roles of BMS and SS in DC development. Jagged-1 and Delta-1 equally activated CBF-1/RBPJ kappa transcription factor, which is a major Notch target. However, they produced a different pattern of activation of Notch target gene Hes1. Overexpression of Hes1 resulted in increased DC differentiation from HPCs. Thus, this study not only revealed the different role of Notch ligands in DC differentiation but also may provide a new insight into regulation of DC differentiation by BMS.