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

Khosravi, Maryam; Bidmeshkipour, Ali; Cohen, José L.; Moravej, Ali; Hojjat-Assari, Suzzan; Naserian, Sina; Karimi, Mohammad Hossein

doi:10.1186/s13287-018-0991-1

Cited by 33 publications

(28 citation statements)

References 61 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In CD4+ T cells, CD40-CD40L binding leads to increased level of IL-10 and IFN-γ [31]; in the presence of IFN-γ, CD40L binding can also lead to the generation of nitric oxide [32]. Additionally, low levels of CD40 expression on dendritic cells leads to marked expansion of T reg cells in a murine model of Leishmania donovani infection [33], and hMSCs promote the development of T reg cells in vitro [34]. Thus, CD40 + hMSCs may simultaneously decrease proliferation of activated T cells while promoting the expression of T reg cells.…”

Section: Plos Onementioning

confidence: 99%

Proinflammatory cytokines and ARDS pulmonary edema fluid induce CD40 on human mesenchymal stromal cells—A potential mechanism for immune modulation

et al. 2020

View full text Add to dashboard Cite

Human mesenchymal stem/stromal cells (hMSCs) are a promising therapy for acute respiratory distress syndrome (ARDS) and other inflammatory conditions. While considerable research has focused on paracrine effects and mitochondrial transfer that improve lung fluid balance, hMSCs are well known to have immunomodulatory properties as well. Some of these immunomodulatory properties have been related to previously reported paracrine effectors such as indoleamine-2,3-dioxygenase (IDO), but these effects cannot fully account for cell-contact dependent immunomodulation. Here, we report that CD40 is upregulated on hMSCs under the same conditions previously reported to induce IDO. Further, CD40 transcription is also upregulated on hMSCs by ARDS pulmonary edema fluid but not by hydrostatic pulmonary edema fluid. Transcription of CD40, as well as paracrine effectors TSG6 and PTGS2 remained significantly upregulated for at least 12 hours after withdrawal of cytokine stimulation. Finally, induction of this immune phenotype altered the transdifferentiation of hMSCs, one of their hallmark properties. CD40 may play an important role in the immunomodulatory effects of hMSCs in ARDS and inflammation.

show abstract

Section: Plos Onementioning

confidence: 99%

Proinflammatory cytokines and ARDS pulmonary edema fluid induce CD40 on human mesenchymal stromal cells—A potential mechanism for immune modulation

et al. 2020

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Valderrama

Han

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Abstract Background: Mesenchymal stem cells (MSCs) display active capacities of suppressing or modulating harmful immune responses through diverse molecular mechanisms. These cells are under extensive translational efforts as cell therapies for immune-mediated diseases and transplantations. A wide range of preclinical studies and limited number of clinical trials using MSCs have not only shown promising safety and efficacy profiles but have also revealed changes in regulatory T cell (T reg) frequency and function. However, the mechanisms underlying this important observation are not well understood. Cell-to-cell contact, production of soluble factors, reprogramming of antigen presenting cells to tolerogenic phenotypes have emerged as possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion. We and others demonstrated that adult bone-marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ (“helper”) and CD8+ (“cytotoxic”) T cells but also indirectly through induction of Tregs. In parallel we demonstrated that fetal liver (FL)-MSCs displays much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs.Methods: MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation and their proliferation potential. Using different in-vitro combinations, we performed co-cultures of FL or BM-MSCs and murine CD3+CD25-T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. Results: We demonstrated that although both types of MSC exhibit similar phenotype profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs.Conclusions: These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.

show abstract

“…MSCs inhibit effector T cell (T eff) proliferation and function in all autologous, allogenic, and xenogeneic conditions while promoting and inducing T regs (iT regs). In consequence, they decrease the secretion of pro-inflammatory cytokine [11]. MSC immunoregulatory function can be changed when exposed to an inflammatory microenvironment.…”

Section: Main Textmentioning

confidence: 99%

TNFα-TNFR2 signaling pathway in control of the neural stem/progenitor cell immunosuppressive effect: Different experimental approaches to assess this hypothetical mechanism behind their immunological function

Shamdani¹,

Uzan²,

Naserian³

2020

Stem Cell Res Ther

Self Cite

View full text Add to dashboard Cite

Background: Stem cells have a vast range of functions from tissue regeneration to immunoregulation. They have the ability to modulate immune responses and change the progression of different inflammatory and autoimmune disorders. Tumor cells share many characteristics of stem/progenitor cells too. Both can inhibit effector T cells and other immune cells, while inducing regulatory T cells (T regs), thus, reducing the production of pro-inflammatory cytokines and increasing the production of anti-inflammatory ones. In this context, some cytokines like TNFα are able to control the direction of the immune response. TNF-TNFR signaling plays a dual role: while the interaction of TNFα with TNFR1 mediates pro-inflammatory effects and cell death, its interaction with TNFR2 mediates antiinflammatory effects and cell survival. Main body: We think the expression of TNFR2 confers a level of immunomodulatory properties to its expressing cell and this could be crucially important, particularly, for stem/progenitor and tumor cells. This idea has been already proven in many TNFR2 + cells. Different immunosuppressive cells like T regs, regulatory B cells (B regs), myeloid-derived suppressor cells (MDSCs), mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) express TNFR2 and are able to suppress immune cells in presence of TNFα. The other category of rare cells that express TNFR2 is neural cells (NCs). Although little is known about the immunological function of these latter cells, few studies showed their progenitors are able to suppress T cells. Therefore, we hypothesize that the immunosuppressive effect of neural stem cells (NSCs) is potentially TNFα-TNFR2 dependent. Conclusions: NSCs are among the rare cells that express TNFR2 marker and are able to supress T cells. We believe TNFα-TNFR2 immune checkpoint signaling pathway could be responsible for this immunosuppressive effect.

show abstract

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

Cited by 33 publications

References 61 publications

Proinflammatory cytokines and ARDS pulmonary edema fluid induce CD40 on human mesenchymal stromal cells—A potential mechanism for immune modulation

Proinflammatory cytokines and ARDS pulmonary edema fluid induce CD40 on human mesenchymal stromal cells—A potential mechanism for immune modulation

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

TNFα-TNFR2 signaling pathway in control of the neural stem/progenitor cell immunosuppressive effect: Different experimental approaches to assess this hypothetical mechanism behind their immunological function

Contact Info

Product

Resources

About