Mesenchymal stem cells (MSCs) are immunoregulatory, and the administration of them has been shown to ameliorate inflammation caused by Th17 cells. However, the mechanisms that contribute to MSC regulation on Th17 cell development are unclear. Here, we found that MSCs could inhibit Th17 cell differentiation through the activation of suppressors of cytokine signaling 3 (SOCS3) when coculture of MSCs and CD4(+)CD25(low)CD44(low)CD62L(high) T cells. Further analysis demonstrated that the inhibitory action was mediated via interferon gamma (IFN-γ), which activated signal transducer and activator of transcription-1 (STAT1) to enhance the expression of SOCS3, leading to STAT3 inhibition. Moreover, stable and reciprocal changes in H3K4me3 and H3K27me3 at the promoters of STAT1, STAT3 and RORγt determined the fate of Th17 cells. These results demonstrate that MSCs may inhibit Th17 differentiation via IFN-γ that activates SOCS3 leading to immunomodulatory effects, suggesting a possible mechanism by which MSCs could act as a cellular approach to attenuate the clinical and pathological manifestations of some autoimmune diseases.

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. In this study, we show that mouse bone marrow–derived Sca-1+Lin−CD117− MSCs can drive HSCs to differentiate into a novel IFN regulatory factor (IRF)8–controlled regDC population (Sca+ BM-MSC–driven DC [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 H3K4me3 methylation 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+ regulatory T cells. Thus, these data infer a possible mechanism for the development of regDCs and further support the role of MSCs in treating immune disorders.

Mesenchymal stem cells (MSCs) have a superior immunomodulatory capacity compared to other cells of the immune system, and they hold great promise for treating various immune disorders. However, their regulatory effects on the maturation of immature dendritic cells (imDCs) are not fully understood. In this study, we show that Sca-1LinCD117MSCs restrain the lipopolysaccharide-stimulated maturation transition of imDCs cocultured without exogenous cytokines. The Notch signaling pathway plays a critical role in the process by controlling interferon regulatory factor 8 (IRF8) expression in an RBP-J-dependent manner. We observed a high degree of H3K27me3 modification mediated by SUZ12 and a relatively low degree of H3K4me3 modification regulated by WDR5 at the IRF8 promoter during coculture. These data reveal a possible mechanism by which Sca-1LinCD117MSCs modulate imDC maturation and further support the role of MSCs in treating immune disorders.