Combination of mesenchymal stem cells and FK506 prolongs heart allograft survival by inhibiting TBK1/IRF3-regulated-IFN-γ production

Abstract Background Muscle stem cells (MuSCs) are absolutely required for the formation, repair, and regeneration of skeletal muscle tissue. Increasing evidence demonstrated that tissue stem cells, especially mesenchymal stem cells (MSCs), can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory properties. Human mesenchymal stem cells (hMSCs) treated with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were reported to possess anti-inflammatory functions by producing TNF-stimulated gene 6 (TSG-6). However, whether human muscle stem cells (hMuSCs) also possess TSG-6 mediated anti-inflammatory functions has not been explored. Methods The ulcerative colitis mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. hMuSCs were pretreated with IFN-γ and TNF-α for 48 h and were then transplanted intravenously at day 2 of DSS administration. Body weights were monitored daily. Indoleamine 2,3-dioxygenase (IDO) and TSG-6 in hMuSCs were knocked down with short hairpin RNA (shRNA) and small interfering RNA (siRNA), respectively. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay (ELISA). Real-time PCR and Western blot analysis were performed to evaluate gene expression. Results hMuSCs treated with inflammatory factors significantly ameliorated inflammatory bowel disease (IBD) symptoms. IDO and TSG-6 were greatly upregulated and required for the beneficial effects of hMuSCs on IBD. Mechanistically, the tryptophan metabolites, kynurenine (KYN) or kynurenic acid (KYNA) produced by IDO, augmented the expression of TSG-6 through activating their common receptor aryl hydrocarbon receptor (AHR). Conclusion Inflammatory cytokines-treated hMuSCs can alleviate DSS-induced colitis through IDO-mediated TSG-6 production.

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Tailored Hydrogels as Delivery Platforms for Conditioned Medium from Mesenchymal Stem Cells in a Model of Acute Colitis in Mice

Pharmaceutics ◽

10.3390/pharmaceutics13081127 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1127

Author(s):

Juan Sendon-Lago ◽

Lorena Garcia-del Rio ◽

Noemi Eiro ◽

Patricia Diaz-Rodriguez ◽

Leandro Avila ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Body Weight ◽

Conditioned Medium ◽

Local Treatment ◽

Histopathological Analysis ◽

Mrna Levels ◽

Acute Colitis ◽

Tnf Α ◽

Ifn Γ

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is increasingly prevalent and current therapies are not completely effective. Mesenchymal stem cells are emerging as a promising therapeutic option. Here, the effect of local hydrogel application loaded with conditioned medium (CM) from human uterine cervical stem cells (hUCESC-CM) in an experimental acute colitis mice model has been evaluated. Colitis induction was carried out in C57BL/6 mice by dissolving dextran sulfate sodium (DSS) in drinking water for nine days. Ulcers were treated by rectal administration of either mesalazine (as positive control) or a mucoadhesive and thermosensitive hydrogel loaded with hUCESC-CM (H-hUCESC-CM). Body weight changes, colon length, and histopathological analysis were evaluated. In addition, pro-inflammatory TNF-α, IL-6, and IFN-γ mRNA levels were measured by qPCR. Treatment with H-hUCESC-CM inhibited body weight loss and colon shortening and induced a significant decrease in colon mucosa degeneration, as well as TNF-α, IFN-γ, and IL-6 mRNA levels. Results indicate that H-hUCESC-CM effectively alleviated DSS-induced colitis in mice, suggesting that H-hUCESC-CM may represent an attractive cell-free therapy for local treatment of IBD.

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Effects of Interferon-γ on Proliferation and Ability of Secretion of Human Amniotic Mesenchymal Stem Cells

Blood ◽

10.1182/blood-2019-125500 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5012-5012

Author(s):

Ya Gao ◽

Ying Xu ◽

Weiru Li ◽

Yintian Zhang ◽

Baohong Ping ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Conflicts Of Interest ◽

Interferon Γ ◽

Cell Counting ◽

Inflammatory Factors ◽

Complete Medium ◽

Amniotic Mesenchymal Stem Cells ◽

Soluble Hla ◽

Ifn Γ

Objective:The immunoregulatory properties and proliferation of mesenchymal stem cells (MSCs) could be affected by inflammatory factors. However, there have been few studies about human amniotic MSCs (hAMSCs). We investigated the effects of interferon (IFN)-γ on the proliferation and apoptosis of hAMSCs, and measured the level of inflammatory factors secreted by hAMSCs. Result:hAMSCs were cultured with complete medium with different concentrations of IFN-γ. We detected the proliferation of hAMSCs by Cell Counting Kit-8 assays, analysed apoptosis by flow cytometry (FCM) at 48 h, and mesasured the level of inflammatory factors such as solube HLA-G and prostaglandin E2 (PGE2) in the supernatant at 48 h by ELISA. The level of kynurenine (KYN) was measured by ultraviolet spectrophotometry. As culture time increased, the proliferation of hAMSCs with different concentrations of IFN-γ increased rapidly from day 1 to day 4, and then the growth rate slowed. FCM indicated that there was no significant apoptosis in the 100 ng/ml IFN-γ group compared with cells without IFN-γ. The level of PGE2 and soluble HLA-G in cells with IFN-γ was higher compared with those without IFN-γ. The level of KYN increased significantly in the cells with IFN-γ. Conclusion:IFN-γ did not affect the growth and proliferation of hAMSCs, and promoted secretion of PGE2 and soluble HLA-G, and enhanced activity of indoleamine 2,3-dioxygenase (IDO), providing a theoretical basis for hAMSCs to prevent and treat graft-versus-host disease. Disclosures No relevant conflicts of interest to declare.

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Cellular Therapy with Donor Mesenchymal Stem Cells Combined with Co-Stimulation Blockade Prolongs Solid Organ Allograft Survival.

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2019.12.454 ◽

2020 ◽

Vol 26 (3) ◽

pp. S259 ◽

Cited By ~ 1

Author(s):

Abraham J. Matar ◽

Brendan P. Lovasik ◽

Steven C. Kim ◽

Cynthia Breeden ◽

David A. Faber ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cellular Therapy ◽

Solid Organ ◽

Allograft Survival

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1,25(OH)2D3 Differently Affects Immunomodulatory Activities of Mesenchymal Stem Cells Depending on the Presence of TNF-α, IL-1β and IFN-γ

Journal of Clinical Medicine ◽

10.3390/jcm8122211 ◽

2019 ◽

Vol 8 (12) ◽

pp. 2211 ◽

Cited By ~ 4

Author(s):

Christian Behm ◽

Alice Blufstein ◽

Johannes Gahn ◽

Barbara Kubin ◽

Michael Nemec ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Inflammatory Cytokines ◽

T Lymphocyte ◽

T Lymphocyte Proliferation ◽

Tnf Α ◽

Ifn Γ ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine ◽

Necrosis Factor

Periodontal ligament-derived mesenchymal stem cells (hPDLSCs) possess immunomodulatory abilities which are strongly enhanced by various inflammatory cytokines. Vitamin D3 has anti-inflammatory effects on hPDLSCs and immune cells. However, no study to date has directly compared the influence of 1,25(OH)2D3 on the immunomodulatory activities of hPDLSCs in the presence of different cytokines. In the present study, the effects of hPDLSCs treated with tumor necrosis factor (TNF)-α, interleukin (IL)-1β, or interferon (IFN)-γ in the presence of 1,25(OH)2D3 on the proliferation of allogenic CD4+ T lymphocyte or on the functional status of primary CD68+ macrophages were analyzed in coculture models. Additionally, the effects of 1,25(OH)2D3 on TNF-α-, IL-1β-, and IFN-γ-induced gene expression of some immunomodulatory factors in hPDLSCs were compared. Under coculture conditions, 1,25(OH)2D3 increased or decreased CD4+ T lymphocyte proliferation via hPDLSCs, depending on the cytokine. hPDLSCs primed with 1,25(OH)2D3 and different cytokines affected pro- and anti-inflammatory cytokine expression in macrophages variably, depending on the priming cytokine. With one exception, 1,25(OH)2D3 significantly reduced TNF-α-, IL-1β-, and IFN-γ-induced expression of all the investigated immunomediators in hPDLSCs, albeit to different extents. These results suggest that 1,25(OH)2D3 influences the immunomodulatory activities of hPDLSCs depending qualitatively and quantitatively on the presence of certain inflammatory cytokines.

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Conditioned immunosuppression makes subtherapeutic cyclosporin effective via splenic innervation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.6.r1710 ◽

1999 ◽

Vol 276 (6) ◽

pp. R1710-R1717 ◽

Cited By ~ 6

Author(s):

Michael S. Exton ◽

Marc Schult ◽

Stefan Donath ◽

Tim Strubel ◽

Ulrike Bode ◽

...

Keyword(s):

Sympathetic Innervation ◽

Conditioning Regimen ◽

Interleukin 2 ◽

Dark Agouti ◽

Allograft Survival ◽

Term Survival ◽

Heart Allograft ◽

Significant Prolongation ◽

Ifn Γ ◽

Behavioral Conditioning

The present study investigated the mechanisms by which conditioned immunosuppression enhances the effectiveness of cyclosporin A (CsA) treatment in prolonging heart allograft survival. Dark Agouti rats that were administered subtherapeutic CsA (7 × 2 mg/kg on alternate days) rejected heart allografts at the same time as non-CsA-treated rats. The addition of a behavioral conditioning regimen (conditioned stimulus, saccharin; unconditioned stimulus, 20 mg/kg CsA) to the subtherapeutic CsA protocol produced a significant prolongation of graft survival, including long-term survival (>100 days) in 20% of the animals. Prior sympathetic denervation of the spleen completely blocked this effect. In nontransplanted rats both conditioning and CsA treatment reduce interleukin-2 and interferon (IFN)-γ in the supernatant of proliferating splenocytes. Additionally, therapeutic CsA treatment decreased the number of IFN-γ-producing CD4+naive and memory T cells in the spleen. In contrast, behavioral conditioning increased that number. These data indicate that behavioral conditioning prolongs heart allograft survival by inhibiting the release of these cytokines in the spleen via sympathetic innervation, supplementing the inhibited cytokine production induced by CsA treatment.

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Induction of Indoleamine 2,3-Dioxygenase Expression by Interferon-g in Human Mesenchymal Stem Cells Inhibits Graft Versus Host Disease

Blood ◽

10.1182/blood.v118.21.4698.4698 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4698-4698

Author(s):

Myoung Woo Lee ◽

Dae Seong Kim ◽

Hye Jin Kim ◽

Meong Hi Son ◽

Soo Hyun Lee ◽

...

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Mesenchymal Stem Cells ◽

T Cell ◽

T Cell Proliferation ◽

Activated T Cells ◽

Graft Versus Host ◽

Ifn Γ ◽

Immunomodulatory Properties

Abstract Abstract 4698 Background: It is important to overcome the limitations such as graft rejection and graft versus host disease (GvHD) in allogeneic hematopoietic stem cell transplantation. Mesenchymal stem cells (MSCs), which evoke only minimal immune reactivity, may have anti-inflammatory and immunomodulatory effects. Purpose: In this study, we aimed to identify the immunomodulatory properties of human MSCs and to elucidate the possible mechanism of their properties for clinical treatment of allogeneic conflicts using MSCs. Materials & Methods: We conducted a comparative analysis about the immunomodulatory properties of MSCs derived from adult human tissues, including bone marrow (BM), adipose tissues (AT), umbilical cord blood (CB), and cord Wharton's jelly (WJ), in vitro and in vivo models. Results: AT-MSCs, CB-MSCs, and WJ-MSCs effectively suppressed phytohemagglutinin (PHA)-induced T-cell proliferation as effectively as did BM-MSCs. Levels of interferon (IFN)-g secreted from activated T-cells increased over time, but these levels were significantly reduced when cocultured with each type of MSCs. In addition, expression of indoleamine 2,3-dioxygenase (IDO) increased in MSCs treated with IFN-γ via JAK/STAT1 signaling pathways. Treatment with anti-IFN-g antibodies, JAK1/2 inhibitor or STAT1 siRNA restored PHA-induced T-cell proliferation. Use of an antagonist, 1-methyl-L-tryptophan, also restored PHA-induced T-cell proliferation, suggesting that IDO contributes to IFN-g-induced immunosuppression in MSCs. Moreover, infusion of IFN-g-treated MSCs decreased symptoms for human peripheral blood-derived mononuclear cells-induced GvHD in NOD/SCID mice, which resulted in an increase of survival rate of in vivo GvHD model. Conclusion: These data indicate that IFN-γ produced by activated T-cells is correlated with induction of IDO expression in MSCs by IFN-γ receptor/JAK/STAT1 pathway, which resulted in suppression of T-cell proliferation. Our findings suggest that MSCs derived from BM, AT, CB, or WJ could be used for clinical treatment of allogeneic conflicts. Disclosures: No relevant conflicts of interest to declare.

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