Induction of CD4+CD25+Foxp3+ regulatory T cells by mesenchymal stem cells is associated with RUNX complex factors

Abstract

Among the particular immunomodulation properties of mesenchymal stem cells (MSCs), one relies on their capacity to regulatory T cell (Treg) induction from effector T cells. Stable expression of Foxp3 has a dominant role in suppressive phenotype and stability of induced regulatory T cells (iTregs). How MSCs induce stable Foxp3 expression in iTregs remains unknown. We previously showed MSCs could enhance demethylation of Treg-specific demethylated region (TSDR) in iTregs in cell-cell contact manner (unpublished data). Here, we evaluated the possible effect of MSCs on the mRNA expression of Runx complex genes (Runx1, Runx3, and CBFB) that perch on TSDR in iTregs and play the main role in suppressive properties of Tregs, a regulatory pathway that has not yet been explored by MSCs. Also, we investigated the mRNA expression of MBD2 that promotes TSDR demethylation in Tregs. We first showed that in vitro MSC-iTreg induction was associated with strong mRNA modifications of genes involved in Runx complex. We next injected high doses of MSCs in a murine model of C57BL/6 into Balb/C allogeneic skin transplantation to prolong allograft survival. When splenocytes of grafted mice were analyzed, we realized that the Foxp3 expression was increased at day 5 and 10 post-graft merely in MSC-treated mice. Furthermore, Foxp3 mRNA expression was associated with modified Runx complex mRNA expression comparable to what was shown in in vitro studies. Hence, our data identify a possible mechanism in which MSCs convert conventional T cells to iTreg through strong modifications of mRNA of genes that are involved in Runx complex of Foxp3.

Induction of CD4+CD25+FOXP3+ regulatory T cells by mesenchymal stem cells is associated with modulation of ubiquitination factors and TSDR demethylation

“…Bone marrow-derived mesenchymal stem cells (BM-MSCs) are capable of modulating the immune response in vitro and in vivo during anti-tumor immune responses, autoimmunity, graft rejection, and graft-versus-host disease (GVHD) [ 14 , 24 , 29 , 30 ]. The immunomodulatory properties of MSCs depend on the production of inhibitory molecules and cytokines (i.e., IL-10, TGF-β, HLA-G, IDO, and PGE2), and on the induction of Tregs and/or tolerogenic dendritic cells (tDCs) [ 24 , 46 ] that are cell–cell contact independent.…”

Human Fetal Liver MSCs are More Effective Than Adult Bone Marrow MSCs for Their Immunosuppressive, Immunomodulatory and Foxp3+ T regs Induction Capacity

“…99,100 We next checked if FL-MSCs, could also exert their immunosuppressive effect indirectly through induction of T regs, as already demonstrated for BM-MSCs. [33][34][35][36][37][38][39][40]101 When CD3/CD28 activated CD3 + CD25 − murine T cells were co-cultured in the presence of either FL or BM-MSCs we observed CD4 + CD25 + Foxp3 + and CD8 + CD25 + Foxp3 + T regs induction with both MSC types. However, very interestingly, in all conditions tested, FL-MSCs induced a higher percentage of T regs than BM-MSCs.…”

“…33 Experimental studies including ours has since been published to con rm this phenomenon and to provide mechanistic aspects. [34][35][36][37][38][39][40] Furthermore, ex vivo expanded MSCs display potent immunomodulatory effects in a wide array of animal disease models and have been validated in clinical trials to represent safe, feasible, and potentially effective immunotherapies for human immune-related disorders including graft-versus-host disease (GVHD) as well as autoimmune diseases. [41][42][43][44] A large number of these animal model studies [45][46][47][48][49][50] and clinical trials [51][52][53][54][55][56][57][58] have also documented changes in T reg number and function after systemic or localized administration of either autologous or allogeneic MSCs.…”

Mesenchymal stem cells: a promising way in therapies of graft-versus-host disease

“…Regarding CD4 + CD25 + FoxP3 + Treg, the crucial factor underlying dramatically modifying the mRNA of genes may be the regulation of MSCs. And Foxp3 complex has some unknown connection with these genes [24]. A considerable amount of literature reports that despite the major role stable Foxp3 expression plays in the phenotype and functional stability of Treg, inflammatory Treg may reduce Foxp3 expression and convert into effector T cells under certain inflammatory conditions.…”

“…A considerable amount of literature reports that despite the major role stable Foxp3 expression plays in the phenotype and functional stability of Treg, inflammatory Treg may reduce Foxp3 expression and convert into effector T cells under certain inflammatory conditions. MSCs can impel the expression of Runt•related transcription factor 1 (RUNX1), RUNX3 and CBFβ complexes in Treg specific demethylation regions through cell-to-cell contact to enhance Foxp3 stability; Foxp3 complex post-transcriptional regulation can induce the transformation of traditional T cells to Treg and amplify Treg's immunosuppressive function [24]. And the number and function of CD8 + CD28-Treg may be enhanced by the stimulation of IL-10,FasL and apoptosis rate decrease resulted from the function of MSCs [25,26].…”