Mesenchymal stem/stromal cells (MSCs) can influence the destiny of hematopoietic stem/progenitor cells (HSCs), and exert broadly immunomodulatory effects on immune cells.However, how MSCs regulate the differentiation of regulatory dendritic cells (regDCs) from HSCs remains incompletely understood.Here,we show that mouse bone marrow (BM)-derived Sca-1+Lin-CD117-MSCs can drive HSCs to differentiate into a novel IRF8-controlled regDC population (sBM-DCs) when cocultured without exogenous cytokines.The Notch pathway plays a critical role in the generation of the sBM-DCs by controlling IRF8 expression in an RBP-J-dependent way.We observed a high level of H3K27me3 methylation and a low level of H3K4me3methylation at the Irf8 promoter during sBM-DC induction.Importantly,infusion of sBM-DCs could alleviate colitis in mice with inflammatory bowel disease by inhibiting lymphocyte proliferation and increasing the numbers of CD4+CD25+Tregs.Thus, these data infer a possible mechanism for the development of regDCs and further support the role of MSCs in treating immune disorders.