Various studies analyzed the inhibitory effect exerted by mesenchymal stem cells (MSCs) on cells of the innate or acquired immunity. Myeloid dendritic cells (DCs) are also susceptible to such inhibition. In this study, we show that MSCs strongly inhibit DC generation from peripheral blood monocytes. In the presence of MSCs, monocytes supplemented with granulocytemacrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) did not acquire the surface phenotype typical of immature (CD14 ؊ , CD1a ؉ ) or mature (CD80 ؉ , CD86 ؉ , CD83 ؉ ) DCs, failed to produce IL-12, and did not induce T-cell activation or proliferation. Analysis of the molecular mechanism(s) responsible for the inhibitory effect revealed a major role of prostaglandin E 2 (PGE 2 ). Thus, addition of the PGE 2 inhibitor NS-398 restored DC differentiation and function. Moreover, PGE 2 directly added to cultures of monocytes blocked their differentiation toward DCs in a manner similar to MSCs.Although IL-6 has been proposed to play a role in MSC-mediated inhibition of DC differentiation, our data indicate that PGE 2 and not IL-6 represents the key inhibitory mediator. Indeed, NS-398 inhibited PGE 2 production and restored DC differentiation with no effect on IL-6 production. These data emphasize the role of MSCs in inhibiting early DC maturation and identifying the molecular mechanisms responsible for the inhibitory effect. (Blood. 2009; 113:6576-6583)
IntroductionHuman mesenchymal stem cells (MSCs) represent a relatively rare stromal cell population that resides primarily in the bone marrow 1 but can be isolated also from other adult and fetal tissues, including adipose tissue, 2 umbilical cord blood, 3 amniotic fluid, 4 and fetal lung. 5 MSCs do not express specific markers but can be phenotypically identified on the basis of the absence of hemopoietic cell markers, namely, CD45, CD34, CD3, CD14, and by the expression of markers, such as CD29, CD90, CD73, CD105, and CD106. 6 MSCs represent multipotent cells capable of differentiating into various lineages, including adipose, osteogenic, and chondrogenic tissues. 7 They secrete several cytokines, growth factors, and extracellular matrix molecules that play an important role in the proliferation and maturation of hematopoietic stem cells (HSCs), thus revealing their potential usefulness for promoting engraftment of HSC transplantation. 8,9 Recently, MSCs have gained attraction not only in regenerative medicine but also in the prevention and treatment of graft-versus-host disease (GVHD) 10-14 thought to reflect their capability (documented in humans, rodents, and primates) of suppressing allogeneic T-cell responses. [15][16][17][18] Subsequent studies further investigated other possible cellular targets of the MSC-mediated immunosuppression. MSCs were shown to exert a strong inhibitory effect on other cells belonging to either innate or adaptive immunity, including natural killer (NK) cells, 19,20 dendritic cells (DCs), 21-23 B cells, 24 and unconventional T cells, including NKT and ␥␦ ϩ cel...