scholarly journals Stem cell product-based blockage of cytokine-induced apoptosis: implications for diabetes

2018 ◽  
Vol 9 (SPL1) ◽  
Author(s):  
Buthainah Al Azzawi ◽  
Catriona Kelly ◽  
Nicholas R Forsyth
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cellular Viability ◽  
Β Cells ◽  
Pancreatic Islets Of Langerhans ◽  
Tnf Α ◽  
Stem Cell Product ◽  
Ifn Γ ◽  
Induced Apoptosis ◽  
Novel Drug

A feature of Type 1 diabetes mellitus (T1DM) is the cytokine-induced apoptosis of insulin-secretingBeta cells (β-cells). The cytokines are secreted from macrophages after infiltration into the pancreatic islets of Langerhans. Daily insulin supplementation is the only widely available treatment option for this disease, but this can lead to serious complications including diabetic ketoacidosis or cardiovascular disease. The utility of mesenchymal stem cells as a therapeutic and novel drug discovery tool is being widely explored. The aim of this study was to explore the therapeutic effectiveness of mesenchymal stem cells (MSC) on cytokine-induced apoptosis in β-cells. BRIN BD11,an insulin-secreting β-cell line was exposed to pro-inflammatory cytokines and endotoxin (IFN-γ,TNF-α,IL-1β and LPS) to induce β-cells apoptosis. This was performed with and without MSC serum-free conditioned media (SF-CM). SF-CM was conditioned for 24 hours on 70% confluent MSC monolayers. Cellular viability and apoptosis were determined with MTT and TUNEL assays respectively. IFN-γ (1μg/ml), TNF-α (100ng/ml),IL-1β (100ng/ml) AND LPS (500 μg/ml) all reduced BRIN BD11 viability to approximately 50% at the concentrations indicated (Figure1A). This effect was noted with and without serum where the latter resulted in decreased sensitivity to TNF-α and LPS. The TUNEL assay confirmed that this reduction in cellular viability resulted from programmed cell death (apoptosis) in all instances (Figure1C). However, the addition of SF-CM significantly decreased the sensitivity of BRIN BD11 cells to all cytokines (P≤0.05) and endotoxin (P≤0.05)in the presence and absence of serum.

scholarly journals Inflammatory cytokines-stimulated human muscle stem cells ameliorate ulcerative colitis via the IDO-TSG6 axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shengchao Zhang ◽  
Jiankai Fang ◽  
Zhanhong Liu ◽  
Pengbo Hou ◽  
Lijuan Cao ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Inflammatory Cytokines ◽  
Human Muscle ◽  
Enzyme Linked Immunosorbent Assay ◽  
Muscle Stem Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory

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.

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

Pharmaceutics ◽  
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.

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

2019 ◽  
Vol 8 (12) ◽  
pp. 2211 ◽  
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.

scholarly journals Secretome of Hypoxic Endothelial Cells Stimulates Bone Marrow-Derived Mesenchymal Stem Cells to Enhance Alternative Activation of Macrophages

2020 ◽  
Vol 21 (12) ◽  
pp. 4409 ◽  
Author(s):  
Kang-Ju Chou ◽  
Chih-Yang Hsu ◽  
Chien-Wei Huang ◽  
Hsin-Yu Chen ◽  
Shih-Hsiang Ou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
Macrophage Polarization ◽  
Alternative Activation ◽  
Cellular Interaction ◽  
Cell Contact ◽  
Tnf Α ◽  
Ifn Γ

We intended to explore the cellular interaction between mesenchymal stem cells (MSCs) and injured endothelial cells leading to macrophage alternative polarization in healing kidney ischemic reperfusion injury. In vivo, the amounts of recruited macrophages were significantly mitigated by MSCs in the injured tissues, especially in the group using hematopoietic cell E- and L-selectin ligand (HCELL)-positive MSCs. Compared to controls, MSCs also enhanced expression of CD206 and CD163, which was further enhanced by HCELL expression. In vitro, analysis of cytokines involving macrophage polarization showed IL-13 rather than IL-4 from MSCs agreed with expression of macrophage CD206 in the presence of hypoxic endothelial cells. Among them, HCELL-positive MSCs in contact with hypoxic endothelial cells produced the greatest response, which were reduced without HCELL or using a transwell to prevent cell contact. With blockade of the respective cytokine, downregulated MSCs secretion of IL-13 and CD206 expression were observed using inhibitors of IFN-γ and TNF-α, but not using those of TGF-β and NO. With IFN-γ and TNF-α, MSCs IL-13 secretion and CD206 expression were upregulated. In conclusion, hypoxia induces endothelial cells producing multiple cytokines. Among them, IFN-γ and TNF-α that stimulate MSCs to secrete IL-13 but not IL-4, leading to alternative polarization.

Overexpression of cellular repressor of E1A-stimulated genes inhibits TNF-α-induced apoptosis via NF-κB in mesenchymal stem cells

2011 ◽  
Vol 406 (4) ◽  
pp. 601-607 ◽  
Author(s):  
Cheng-Fei Peng ◽  
Ya-Ling Han ◽  
Jie-Deng ◽  
Cheng-Hui Yan ◽  
Jian-Kang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tnf Α ◽  
Induced Apoptosis

scholarly journals IDO and CD40 May Be Key Molecules for Immunomodulatory Capacity of the Primed Tonsil-Derived Mesenchymal Stem Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 5772
Author(s):  
Hyun-Joo Lee ◽  
Harry Jung ◽  
Dong-Kyu Kim
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Suppressive Effect ◽  
Tnf Α ◽  
Immunomodulatory Capacity ◽  
Ifn Γ

Background: Tonsil-derived mesenchymal stem cells (T-MSCs) were reported to have suppressive effect on T cells, yet much remains unknown about the underlying mechanisms supporting this effect. We investigated the underlying mechanism of the immunomodulatory effect of T-MSCs on immune cell proliferation and cytokine production. Methods: We isolated T-MSCs from human palatine tonsil and evaluated the immunomodulatory capacity using RT-PCR, ELISA, and flow cytometry. Additionally, we assessed the expression of various soluble factors and several costimulatory molecules to detect the priming effect on T-MSCs. Results: T-MSCs significantly inhibited the immune cell proliferation and cytokine expression (TNF-α and IFN-γ) in the direct co-culture, but there was no suppressive effect in indirect co-culture. Additionally, we detected a remarkably higher expression of indoleamine 2,3-dioxygenase (IDO) in the primed T-MSCs having co-expression CD40. Moreover, immune cells or CD4+ T cells showed lower TNF-α, IFN-γ, and IL-4 expression when the primed T-MSC were added; whereas those findings were reversed when the inhibitor for IDO (not IL-4) or CD40 were added. Furthermore, T-bet and GATA3 levels were significantly decreased in the co-cultures of the primed T-MSCs and CD4+ T cells; whereas those findings were reversed when we added the neutralizing anti-CD40 antibody. Conclusions: Primed T-MSCs expressing IDO and CD40 may have immunomodulatory capacity via Th1-mediated and Th2-mediated immune response.

scholarly journals CEBPA exerts a specific and biologically important proapoptotic role in pancreatic β cells through its downstream network targets

2014 ◽  
Vol 25 (16) ◽  
pp. 2333-2341 ◽  
Author(s):  
Davide Barbagallo ◽  
Angelo Giuseppe Condorelli ◽  
Salvatore Piro ◽  
Nunziatina Parrinello ◽  
Tina Fløyel ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
In Silico Analysis ◽  
Causal Role ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Nfkb Pathway ◽  
Induced Apoptosis ◽  
Silico Analysis

Transcription factor CEBPA has been widely studied for its involvement in hematopoietic cell differentiation and causal role in hematological malignancies. We demonstrate here that it also performs a causal role in cytokine-induced apoptosis of pancreas β cells. Treatment of two mouse pancreatic α and β cell lines (αTC1-6 and βTC1) with proinflammatory cytokines IL-1β, IFN-γ, and TNF-α at doses that specifically induce apoptosis of βTC1 significantly increased the amount of mRNA and protein encoded by Cebpa and its proapoptotic targets, Arl6ip5 and Tnfrsf10b, in βTC1 but not in αTC1-6. Cebpa knockdown in βTC1 significantly decreased cytokine-induced apoptosis, together with the amount of Arl6ip5 and Tnfrsf10b. Analysis of the network comprising CEBPA, its targets, their first interactants, and proteins encoded by genes known to regulate cytokine-induced apoptosis in pancreatic β cells (genes from the apoptotic machinery and from MAPK and NFkB pathways) revealed that CEBPA, ARL6IP5, TNFRSF10B, TRAF2, and UBC are the top five central nodes. In silico analysis further suggests TRAF2 as trait d'union node between CEBPA and the NFkB pathway. Our results strongly suggest that Cebpa is a key regulator within the apoptotic network activated in pancreatic β cells during insulitis, and Arl6ip5, Tnfrsf10b, Traf2, and Ubc are key executioners of this program.

IFN-γ and TNF-α differentially regulate immunomodulation by murine mesenchymal stem cells

2007 ◽  
Vol 110 (2) ◽  
pp. 91-100 ◽  
Author(s):  
Karen English ◽  
Frank P. Barry ◽  
Ciara P. Field-Corbett ◽  
Bernard P. Mahon
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tnf Α ◽  
Ifn Γ

scholarly journals Immunomodulatory Effect of Human Umbilical Cord Blood-derived Mesenchymal Stem Cells on Activated T-lymphocyte

2021 ◽  
Author(s):  
Parisa Lotfinejad ◽  
Karim Shamsasenjan ◽  
Behzad Baradaran ◽  
Elham Safarzadeh ◽  
Tohid Kazemi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
T Lymphocytes ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Immunomodulatory Effects ◽  
Tnf Α ◽  
Activated T Lymphocytes ◽  
Ifn Γ

Many studies have been performed about regenerative and immunomodulatory properties of mesenchymal stem cells (MSCs) and their application in different treatment approaches. The present study aimed to investigate the immunomodulatory effect of umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) on the gene expression profile of cytokines in stimulated T-lymphocytes. For this purpose, MSCs were isolated from umbilical cord blood samples and cultured in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum. The nature of MSCs was identified by flow cytometry analysis and differentiation to the adipocyte and osteocyte lineage. Moreover, to investigate the immunomodulatory effects of MSCs on T cells, a co-culture system was designed and expression levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-13, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) genes were measured; using the real-time polymerase chain reaction (RT-PCR) technique. Our results demonstrated the ability of MSCs to differentiate into adipocyte and osteocyte lineages. Further investigation also displayed that although UCB-MSCs could significantly reduce the expression of pro-inflammatory cytokines like IL-2, IL-6, IFN-γ, and TNF-α in activated T-lymphocytes, they noticeably potentiated the expression levels of IL-4, IL-10, IL-13, and TGF-β in the co-culture setting. In conclusion, UCB-MSCs have immunomodulatory effects on activated T-lymphocytes in favor of anti-inflammatory responses.

IFN-γ, Unlike TNF-α, LPS, or CD40 Signal, Is Required and Sufficient To Induce Indoleamine 2,3-Dioxygenase Activity in Mesenchymal Stem Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2311-2311
Author(s):  
Karin Tarte ◽  
Delphine Monnier ◽  
Patricia Ame-Thomas ◽  
Joelle Dulong ◽  
Céline Bonnaventure ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Dependent Manner ◽  
Clinical Grade ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Immunological Properties ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tnf Α ◽  
Ifn Γ

Abstract In addition to their extensive proliferation and differentiation potential, adult bone-marrow derived mesenchymal stem cells (MSC) have been recently demonstrated to display non-HLA restricted immunosuppressive capacities in vitro. Accordingly, preliminary clinical trials have begun using MSC for prevention or treatment of acute graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation setting. However, very few conclusive data are currently available concerning i) the mechanisms of MSC-mediated immunomodulation, ii) the migration and engraftment of infused MSC, and iii) the influence of cellular environment and soluble factors on their outcome and immunological properties, especially in the context of GVHD-associated inflammation. Using a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), we first confirmed the major implication of this enzyme in the MSC-dependent inhibition of PBMC and purified T cell alloantigen-induced proliferation. Such results were extended to clinical-grade MSC generated in a large scale closed culture system in the presence of clinical-grade fetal calf serum and basic fibroblast growth factor. In addition, MSC exerted the same dose-response anti-proliferative effect either they were third-party or autologous to MLR-responder cells and irradiated or non-irradiated. We could not point out in this system a role for PGE2, despite the use of two well-known inhibitors, or for membrane and soluble HLA-G molecules. Moreover, we shown that IFN-γ was sufficient to trigger, in a dose-dependent manner, the simultaneous induction of IDO expression, at the mRNA and protein levels, and IDO activity, evaluated through the measurement of tryptophan/kynurenine ratio by HPLC. On the contrary, purified peripheral blood monocytes constitutively expressed an inactive form of IDO, and IFN-γ operated only at posttranscriptionnal level in these cells. Antagonist anti-IFN-γ MoAb blocked the induction of IDO activity induced on MSC by allogeneic MLR supernatant, suggesting that IFN-γ is absolutely required for induction of IDO in MSC during immune response. TNF-α and LPS also modulated MSC immune functions through induction of a complex set of genes, such as those coding for CXCL9, CXCL10, and CCL5 inflammatory chemokines involved in GVHD. However, they could not induce IDO activity. CD40 marker was always detected at the beginning of clinical-grade MSC culture. It was lost after several passages but remained inducible by IFN-γ and TNF-α. Treatment of MSC by trimeric CD40L induced expression of several genes involved in immune reaction, such as BAFF, but not CD80 and CD86 costimulatory molecules or IDO. In conclusion, IDO is an essential factor for immunosuppressive properties of clinical-grade MSC. Inflammatory cytokines, LPS, and contact with activated CD40Lpos T cells could markedly alter immunological properties of MSC. Such modifications must be taken into account for their further use as immunomodulator treatments in GVHD context.

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