Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IL-10–Dependent Regulatory Dendritic Cells by SOCS3 Activation

Abstract

Suppression of immune response by mesenchymal stem/stromal cells (MSCs) is well documented. However, their regulatory effects on immune cells, especially regulatory dendritic cells, are not fully understood. We have identified a novel Sca-1+Lin−CD117− MSC population isolated from mouse embryonic fibroblasts (MEF) that suppressed lymphocyte proliferation in vitro. Moreover, the Sca-1+Lin−CD117− MEF-MSCs induced hematopoietic stem/progenitor cells to differentiate into novel regulatory dendritic cells (DCs) (Sca-1+Lin−CD117− MEF-MSC–induced DCs) when cocultured in the absence of exogenous cytokines. Small interfering RNA silencing showed that Sca-1+Lin−CD117− MEF-MSCs induced the generation of Sca-1+Lin−CD117− MEF-MSC–induced DCs via IL-10–activated SOCS3, whose expression was regulated by the JAK–STAT pathway. We observed a high degree of H3K4me3 modification mediated by MLL1 and a relatively low degree of H3K27me3 modification regulated by SUZ12 on the promoter of SOCS3 during SOCS3 activation. Importantly, infusion of Sca-1+CD117−Lin− MEF-MSCs suppressed the inflammatory response by increasing DCs with a regulatory phenotype. Thus, our results shed new light on the role of MSCs in modulating regulatory DC production and support the clinical application of MSCs to reduce the inflammatory response in numerous disease states.

Galectin-9 Is a Suppressor of T and B Cells and Predicts the Immune Modulatory Potential of Mesenchymal Stromal Cell Preparations

“…For T reg cells the described effects are rather different. As described in various in vitro and in vivo models MSCs increased T reg levels via Gal-9 independent mechanisms such as TGF-b or PGE 2 [45,46]. Surprisingly, Gal-9 and activated MSCs restored or even decreased T reg cell counts.…”

Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

“…Analogous to the effects of MSCs on macrophage polarization, MSCs can also promote the generation of tolerogenic DCs (Li et al 2008a;Ge et al 2009;Spaggiari et al 2009;Zhang et al 2009;Liu et al 2012b) producing anti-inflammatory cytokines and displaying enhanced phagocytic activity Liu et al 2012b) typical of tolerogenic DCs. MSC educated DCs have the capacity to suppress alloreactive responses and prolong islet allograft survival (Huang et al 2010) and to induce a state of tolerance in the context of SOT (cardiac allograft) in the presence of low dose immunosuppression (Ge et al 2009).…”

“…Further evidence of a contact-dependent mechanism involving activation of AKT and impaired NF-kB signaling has been proposed (Chiesa et al 2011). Finally, it has been shown that mouse embryonic fibroblast derived MSCs generate a novel population of IL-10 dependent tolerogenic DCs through an IL-10 activated SOCS3 dependent mechanism (Liu et al 2012b). MSC induction of tolerogenic DCs is a key mechanism involved in MSC modulation of immune responses; however, significant gaps in our understanding of exactly how MSCs promote the generation of tolerogenic DCs remain.…”

Sca-1+Lin−CD117− Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IRF8-Controlled Regulatory Dendritic Cells through Notch–RBP-J Signaling

“…MSCs were prepared and purified from mouse BM cells as previously described (37,38). Mouse immature DCs (imDCs) and mature DCs (maDCs) were generated according to previously published protocols (39).…”

“…The protein expression level was analyzed by Western blot as previously described (38). Abs were obtained from Cell Signaling Technology.…”