Human Mesenchymal Stem Cells Impact Th17 and Th1 Responses Through a Prostaglandin E2 and Myeloid-Dependent Mechanism

Rozenberg, Ayal; Rezk, Ayman; Boivin, Marie-Noëlle; Darlington, Peter J.; Nyirenda, Mukanthu; Li, Rui; Jalili, Farzaneh; Winer, Raz; Artsy, Elinor A.; Uccelli, Antonio; Reese, Jane; Planchon, Sarah M.; Cohen, Jeffrey A.; Bar‐Or, Amit

doi:10.5966/sctm.2015-0243

Cited by 69 publications

(57 citation statements)

References 52 publications

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“…Haribhai et al showed that TGF-b-producing M2a macrophages differentiated Th17 cells into anti-inflammatory iTreg cells (Haribhai et al, 2016). For MSCs and Th17 interactions, Qu et al reported that Th17 cells were suppressed by IL-10 secreted by MSCs (Qu et al, 2012), Rozenberg et al showed that PGE2 secreted from MSCs increased the Th17 response but suppressed the Th1 response (Rozenberg et al, 2016), and Ghannam et al noted that MSCs increased Treg cells by suppressing Th17 cells (Ghannam et al, 2010). Our findings revealed that the Th17 frequencies of the A-PBMC group was significantly higher than those of the remaining groups, except M1 and M2c.…”

Section: Discussionsupporting

confidence: 47%

The investigation of immunomodulatory effects of adipose tissue mesenchymal stem cell educated macrophages on the CD4 T cells

Özdemir¹,

Özdemir²,

Sarıboyacı³

et al. 2019

Immunobiology

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Keywords:Mesenchymal stem cell M1 macrophage M2 macrophage Th1 Th2 Th17 Treg Immunomodulation A B S T R A C T Mesenchymal stem cells (MSCs) are strong immunomodulatory cells investigated in numerous clinical studies on fatal pathologies, such as graft versus host disease and autoimmune diseases; e.g., systemic lupus erythematosus, Crohn's disease, and ulcerative colitis. Macrophages are one of the critical cells linking the innate and adaptive immune system, and it has been shown that MSCs can differentiate between pro-inflammatory M1 phenotype and anti-inflammatory M2 phenotype of macrophages. However, it has not yet been fully clarified whether these differentiated macrophages are functional. In this study, we compared the immunomodulatory effects on the CD4 T cells of M1, M2a and M2c macrophages with the macrophages that directly and indirectly cultured with MSCs. We analyzed the changes in CD14, CD64, CD80, CD163 and CD200R expression to evaluate macrophage phenotypes, and the changes in CD4, IFN-g, IL-4, IL-17a and FoxP3 expression to evaluate T helper subsets using the FACS method. The changes in IL-1b, IL-4, IL-10, IL-12p70, IL-17a and IFN-g in the media supernatants were analyzed using the Luminex method. We also performed WST-1 and Caspase-3 ELISA analyses to observe the proliferation and apoptosis status of the T cells. MSCs were found to differentiate macrophages into a distinctive phenotype, which was close to the M2c phenotype, but was not considered as an M2c cell due to the low expression of CD163, a characteristic marker for M2c. While MEM-D, MEM-ID and MSCs showed similar inhibitory effects on the Th2 and Th17 cells, the most significant increase in Treg cell frequencies was seen in MEM-D cells. Macrophages can alter their phenotypes and functions according to the stimuli from the environment. The fact that macrophages educated with MSCs suppressed the production of all the cytokines we evaluated even after the removal of MSCs suggests that these cells may be differentiated by MSCs into a suppressive macrophage subgroup. However, the Treg cell activation caused by direct interactions between MSCs and macrophage cells may be the most prominent observation of this study compared to previous work. As a result, according to our data, the interactions between MSCs and macrophages may lead to differentiation of macrophage cells into an immunosuppressive phenotype, and these macrophages may suppress the T lymphocyte subgroups at least as effectively as MSCs. However, our data obtained from in vitro experiments should be supported by future in vivo studies.

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Section: Discussionsupporting

confidence: 47%

The investigation of immunomodulatory effects of adipose tissue mesenchymal stem cell educated macrophages on the CD4 T cells

Özdemir¹,

Özdemir²,

Sarıboyacı³

et al. 2019

Immunobiology

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“…Another example of reciprocal regulation was seen with prostaglandin E2 (PGE 2 ), a proinflammatory chemical that signals through a G‐protein‐coupled receptor. PBMCs treated with PGE 2 produced more IL‐17A and less IFNγ . Reciprocal regulation also occurred when Th17 cells were cultured with mesenchymal stem cells that produced and secreted PGE 2 .…”

Section: Discussionmentioning

confidence: 90%

“…PBMCs treated with PGE 2 produced more IL‐17A and less IFNγ . Reciprocal regulation also occurred when Th17 cells were cultured with mesenchymal stem cells that produced and secreted PGE 2 . Thus, agents that cause G protein signaling and elevate cAMP tend to promote IL‐17A responses while inhibiting IFNγ.…”

Section: Discussionmentioning

confidence: 97%

Reciprocal modulation of helper Th1 and Th17 cells by the β2‐adrenergic receptor agonist drug terbutaline

et al. 2017

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Catecholamine hormones are powerful regulators of the immune system produced by the sympathetic nervous system (SNS). They regulate the adaptive immune system by altering T-cell differentiation into T helper (Th) 1 and Th2 cell subsets, but the effect on Th17 cells is not known. Th17 cells, defined, in part, by chemokine receptor CCR6 and cytokine interleukin (IL)-17A, are crucial for mediating certain pathogen-specific responses and are linked with several autoimmune diseases. We demonstrated that a proportion of human Th17 cells express beta 2-adrenergic receptor (β2AR), a G protein-coupled receptor that responds to catecholamines. Activation of peripheral blood mononuclear cells, which were obtained from venous blood drawn from healthy volunteers, with anti-cluster of differentiation 3 (CD3) and anti-CD28 and with a β2-agonist drug, terbutaline (TERB), augmented IL-17A levels (P < 0.01) in the majority of samples. TERB reduced interferon gamma (IFNγ) indicating that IL-17A and IFNγ are reciprocally regulated. Similar reciprocal regulation was observed with dbcAMP. Proliferation of Th cells was monitored by carboxyfluorescein diacetate N-succinimidyl ester labeling and flow cytometry with antibody staining for CD3 and CD4. TERB increased proliferation by a small but significant margin (P < 0.001). Next, Th17 cells (CD4 CXCR3 CCR6 ) were purified using an immunomagnetic positive selection kit, which removes all other mononuclear cells. TERB increased IL-17A from purified Th17 cells, which argues that TERB acts directly on Th17 cells. Thus, hormone signals from the SNS maintain a balance of Th cells subtypes through the β2AR.

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“…Indeed, the clinical applications of allogeneic mesenchymal stem cells include organ transplantation and the treatment of multiple sclerosis, graft versus host disease and Crohn's disease 30 . Interestingly, mediation of the regulatory effect of mesenchymal stem cells on Th1 and Th17 responses by CD14 + myeloid cells and the production of PGE 2 was recently reported 31 . Confirmation of the reduced allogenicity of MDSCs in appropriate in vivo models would open the door to the therapeutic use of ex vivo ‐ or in vivo ‐generated allogeneic or third‐party MDSCs.…”

Section: Discussionmentioning

confidence: 99%

“…30 Interestingly, mediation of the regulatory effect of mesenchymal stem cells on Th1 and Th17 responses by CD14 + myeloid cells and the production of PGE 2 was recently reported. 31 Confirmation of the reduced allogenicity of MDSCs in appropriate in vivo models would open the door to the therapeutic use of ex vivoor in vivo-generated allogeneic or third-party MDSCs. In general, the pattern of cytokines secreted in cocultures of MDSCs and allogeneic PBMCs was consistent with the immunomodulatory activity of these cells.…”

Section: Discussionmentioning

confidence: 99%

Myeloid‐derived suppressor cells can be efficiently generated from human hematopoietic progenitors and peripheral blood monocytes

et al. 2017

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Myeloid-derived suppressor cells (MDSCs) have an important role in controlling inflammation. As such, they are both a therapeutic target and, based on the administration of ex vivo-generated MDSCs, a therapeutic tool. However, there are relatively few reports describing methods to generate human MDSCs, and most of them rely on cells obtained from peripheral blood monocytes. We investigated alternative approaches to the generation of MDSCs from hematopoietic progenitors and monocytes. Purified CD34 hematopoietic progenitors from apheresis products and CD14 cells isolated from buffy coats were cultured in the presence of different combinations of cytokines. The resulting myeloid cell populations were then characterized phenotypically and functionally. Progenitor cells cultured in the presence of SCF+TPO+FLT3-L+GM-CSF+IL-6 gave rise to both monocytic (M)- and granulocytic (G)-MDSCs but production of the latter was partially inhibited by IL-3. M-MDSCs but not G-MDSCs were obtained by culturing peripheral blood monocytes with GM-CSF+IL-6 or GM-CSF+TGF-β1 for 6 days. CD14 expression was downregulated in the cultured cells. PD-L1 expression at baseline was lower in hematopoietic progenitor cell-derived than in monocyte-derived MDSCs, but was markedly increased in response to stimulation with LPS+IFN-γ. The functionality of the two MDSC subtypes was confirmed in studies of the suppression of allogeneic and mitogen-induced proliferation and by cytokine profiling. Here we describe both the culture conditions that allow the generation of MDSCs and the phenotypical and functional characterization of these cell populations.

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Human Mesenchymal Stem Cells Impact Th17 and Th1 Responses Through a Prostaglandin E2 and Myeloid-Dependent Mechanism

Cited by 69 publications

References 52 publications

The investigation of immunomodulatory effects of adipose tissue mesenchymal stem cell educated macrophages on the CD4 T cells

The investigation of immunomodulatory effects of adipose tissue mesenchymal stem cell educated macrophages on the CD4 T cells

Reciprocal modulation of helper Th1 and Th17 cells by the β2‐adrenergic receptor agonist drug terbutaline

Myeloid‐derived suppressor cells can be efficiently generated from human hematopoietic progenitors and peripheral blood monocytes

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