Mesenchymal Stem Cells Inhibit Generation and Function of Both Monocyte-Derived and CD34-Derived Dendritic Cells.

Abstract

Mesenchymal stem cells (MSCs) have been demonstrated to exert profound immunosuppressive properties on T cell proliferation. However, their effect on the initiators of the immune response, the dendritic cells (DCs), are relatively unknown. In the present study, the effects of MSCs on the differentiation and function of both monocyte-derived DCs and CD34+-derived DCs were investigated. Monocytes (CD1a-CD14+) were obtained from PB and were cultured with IL-4 and GM-CSF to induce differentiation into CD14-CD1a+ immature DCs. CD34+ hematopoietic progenitor cells were isolated from umbilical cord blood samples and cultured in the presence of GM-CSF, TNF-a, and SCF to generate Langerhans cells, which differentiate directly into CD1a+ DCs, and dermal/interstitial DCs, which differentiate via an intermediate CD14+CD1a- phenotype into CD14-CD1a+ DCs. MSCs were generated from fetal lung tissue as reported previously (Exp. Hematol.2002; 30: 870–878). The phenotype (CD1a, CD14, CD80, CD86, CD83, HLA-DR, CD40) of the cells was analyzed by flow cytometry; cytokine production (IL-12, TNF-α) was examined by enzyme-linked immunosorbent assay (ELISA) and T cell stimulatory capacity was determined by a mixed lymphocyte reaction (MLR). The presence of MSCs during the complete differentiation period completely prevented the generation of immature DCs (CD1a+CD14-) from monocytes in a dose-dependent manner. MSCs in the upper wells of a transwell culture system inhibited the differentiation of monocytes in the lower wells, indicating that the suppressive effect of MSCs was mediated via soluble factors. The inhibitory effect of MSCs on the differentiation of DCs was partially prevented by the addition of neutralizing antibodies to IL-6 and M-CSF, indicating the involvement of these cytokines. Upon removal of MSCs cultured in a transwell after 48h, differentiation of monocytes towards DCs was restored, indicating that the suppressive effect of MSCs was reversible. DCs generated in the presence of MSCs were unresponsive to signals inducing maturation (CD40 ligand, lipopolysaccharide), as demonstrated by the absence of CD83, CD80, CD86 and HLA-DR upregulation and the decreased production of the inflammatory cytokines TNF-α (76%) and IL-12 (79%). In addition, the T cell stimulatory capacity of mature DCs generated in the presence of MSCs was strongly reduced. MSCs also inhibited the generation of DCs from CD34+ progenitor cells by blocking the differentiation of CD14+CD1a- precursors into dermal/interstitial DCs, without affecting the generation of CD1a+ Langerhans cells. The inhibitory effect of MSCs on CD34+ cell differentiation was dose-dependent and resulted in both phenotypical and functional modifications, as demonstrated by a reduced expression of costimulatory molecules (CD80, CD86) and CD83, and hampered capacity to stimulate naïve T-cell proliferation (50,112 ± 1,305 cpm versus 20,412 ± 1,593 cpm). Taken together, these data demonstrate that MSCs, next to the anti-proliferative effect on T cells, have a profound inhibitory effect on the generation and function of both monocyte- and CD34+-derived DCs, indicating that MSCs are able to modulate immune responses at multiple levels.

Immunosuppressive properties of human umbilical cord‐derived mesenchymal stem cells: role of B7‐H1 and IDO

“…Several reports have shown that MSCs have the ability to interfere with DC differentiation and maturation, from both CD34 + bone marrow cells and CD14 + monocytes. 35,36 In this study we have shown that co-culturing of monocytes with UCMSCs prevented the CD14 + cells to differentiate and mature to DCs. Although the monocytes acquired antigens such as CD209, CD86 and B7-H1, all known to be expressed on imDCs, these cells failed to downregulate CD14 antigen in the presence of UCMSCs.…”

Mesenchymal stem cells alleviate bacteria‐induced liver injury in mice by inducing regulatory dendritic cells

“…Several studies demonstrated previously that MSCs might interfere with the differentiation of CD34 1 HPC into mature DCs. 11,12 Recently, Li et al 30 showed that human bone marrow-derived MSCs may induce HPCs to generate regulatory DCs through activation of the Notch pathway. Liu et al 11 reported that embryonic fibroblast-derived MSCs induced generation of mouse regulatory DCs from HPCs by activation of SOCS3 in a IL-10-dependent manner.…”

“…10 Recently, several groups reported that MSCs may drive the differentiation of regulatory DCs from HPCs. 11,12 However, the underlying mechanisms are still poorly understood and the induction of regulatory DCs in vivo remains controversial.…”

The pro‐metastatic role of bone marrow‐derived cells: a focus on MSCs and regulatory T cells

“…Human MSCs suppress the proliferation of T cells through mediators such as TGF-β and HGF [125], and induce apoptosis of activated T cells through indoleamine 2,3-dioxygenase secretion [126]. MSCs also interfere with dendritic cell differentiation [127][128][129], which is crucial for the production of pro-inflammatory cytokines-including TNF-α, IFN-γ and IL-12-as well as B-and NK-cell proliferation [130,131]. This markedly hampers the normal inflammatory function of immune cells (Fig 2).…”