Microglia are the primary immunocompetent cells in brain tissue and microglia-mediated inflammation is associated with the pathogenesis of various neuronal disorders. Recently, many studies have shown that mesenchymal stem cells (MSCs) display a remarkable ability to modulate inflammatory and immune responses through the release of a variety of bioactive molecules, thereby protecting the central nervous system. Previously, we reported that MSCs have the ability to modulate inflammatory responses in a traumatic brain injury model and that the potential mechanisms may be partially attributed to upregulated TNF-α stimulated gene/protein 6 (TSG-6) expression. However, whether TSG-6 exerts an anti-inflammatory effect by affecting microglia is not fully understood. In this study, we investigated the anti-inflammatory effects of MSCs and TSG-6 in an in vitro lipopolysaccharide (LPS)-induced BV2 microglial activation model. We found that MSCs and TSG-6 significantly inhibited the expression of pro-inflammatory mediators in activated microglia. However, MSC effects on microglia were attenuated when TSG-6 expression was silenced. In addition, we found that the activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways in LPS-stimulated BV2 microglial cells was significantly inhibited by TSG-6. Furthermore, we found that the presence of CD44 in BV2 microglial cells was essential for MSC- and TSG-6-mediated inhibition of pro-inflammatory gene expression and of NF-κB and MAPK activation in BV2 microglial cells. The results of this study suggest that MSCs can modulate microglia activation through TSG-6 and that TSG-6 attenuates the inflammatory cascade in activated microglia. Our study indicates that novel mechanisms are responsible for the immunomodulatory effect of MSCs on microglia and that MSCs, as well as TSG-6, might be promising therapeutic agents for the treatment of neurotraumatic injuries or neuroinflammatory diseases associated with microglial activation.

Human amniotic membrane-derived mesenchymal stem cells (AMSCs) are considered a novel and promising source of stem cells for cell replacement-based therapy. Current research is mostly limited to investigating the cellular differentiation potential of AMSCs, while few have focused on their immunosuppressive properties. This study is aimed at exploring and evaluating the immunosuppressive effect of human AMSCs on the viability and migratory properties of microglia. We found, from results of cell viability assays, that AMSCs can reduce the activity of inflammatory cells by secreting nitric oxide (NO). Also, based on results from wound healing and transwell migration assays, we show that AMSCs can inhibit the migration of human microglia as well as the mouse microglial cell line BV2, suggesting that they have the ability to inhibit the recruitment of certain immune cells to injury sites. Furthermore, we found that NO contributes significantly to this inhibitory effect. Our study provides evidence that human AMSCs can have detrimental effects on the viability and migration of microglia, through secretion of NO. This mechanism may contribute to anti-inflammatory processes in the central nervous system.

Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that are characterized by the ability to take up and process antigens and prime T cell responses. Mesenchymal stem cells (MSCs) are multipotent cells that have been shown to have immunomodulatory abilities, including inhibition of DC maturation and function in vivo and in vitro; however, the underlying mechanism is far from clear. In this study we found that MSCs can inhibit the maturation and function of bone marrow-derived DCs by releasing TSG-6. In the presence of MSCs, lower expression of mature DC surface phenotype (CD80, CD86, MHC-II, and CD11c) was observed. In addition, typical DC functions, such as the production of IL-12 and the ability to prime T cells, were decreased when co-cultured with MSCs. In contrast, knockdown of TSG-6 reduced the inhibitory effect of MSCs on DC. Moreover, we found that TSG-6 can suppress the activation of MAPKs, and NF-κB signaling pathways within DCs during Lipopolysaccharides (LPS) stimulation. In conclusion, we suggest that TSG-6 plays an important role in MSCs-mediated immunosuppressive effect on DC.

Objective To investigate whether bone marrow-derived mesenchymal stem cells (BMSCs) influence the activity of microglias after lipopolysaccharide (LPS) stimulation and explore the mechanism of BMSCs in treating central nervous system injury.Methods The best stimulation LPS concentration for microglias secretion was determined; four groups,as blank control group,LPS stimulation group,BMSCs stimulation group and LPS+BMSCs stimulation group,were chosen in our study.The proliferation of activated microglias was detected by CCK-8,phagocytosis of activated microglias was detected by phagocytosis of fluorescent microspheres experiment and pro-inflammatory factors secretion changes of activated micmglias were observed by Bio-Plex Pro assays and griess reagent.Results As compared with those in the blank control group,the proliferation and phagocytosis of activated microglias in the BMSCs stimulation group were significantly inhibited (P=0.000,P=0.033); so as to the proinflammatory factors secretion of activated microglias in the BMSCs stimulation group (P＜0.05).Conclusion BMSCs have the ability to control microglial activation,indicating that BMSCs could be a promising therapeutic tool for treatment of diseases associated with microglial activation.

BACKGROUND:Previous studies have shown beneficial effects of mesenchymal stem cell (MSC) transplantation in central nervous system (CNS) injuries, including traumatic brain injury (TBI). Potential repair mechanisms involve transdifferentiation to replace damaged neural cells and production of growth factors by MSCs. However, few studies have simultaneously focused on the effects of MSCs on immune cells and inflammation-associated cytokines in CNS injury, especially in an experimental TBI model. In this study, we investigated the anti-inflammatory and immunomodulatory properties of MSCs in TBI-induced neuroinflammation by systemic transplantation of MSCs into a rat TBI model.METHODS/RESULTS:MSCs were transplanted intravenously into rats 2 h after TBI. Modified neurologic severity score (mNSS) tests were performed to measure behavioral outcomes. The effect of MSC treatment on neuroinflammation was analyzed by immunohistochemical analysis of astrocytes, microglia/macrophages, neutrophils and T lymphocytes and by measuring cytokine levels [interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-α, interferon-γ, RANTES, macrophage chemotactic protein-1, macrophage inflammatory protein 2 and transforming growth factor-β1] in brain homogenates. The immunosuppression-related factors TNF-α stimulated gene/protein 6 (TSG-6) and nuclear factor-κB (NF-κB) were examined by reverse transcription-polymerase chain reaction and Western blotting. Intravenous MSC transplantation after TBI was associated with a lower density of microglia/macrophages and peripheral infiltrating leukocytes at the injury site, reduced levels of proinflammatory cytokines and increased anti-inflammatory cytokines, possibly mediated by enhanced expression of TSG-6, which may suppress activation of the NF-κB signaling pathway.CONCLUSIONS:The results of this study suggest that MSCs have the ability to modulate inflammation-associated immune cells and cytokines in TBI-induced cerebral inflammatory responses. This study thus offers a new insight into the mechanisms responsible for the immunomodulatory effect of MSC transplantation, with implications for functional neurological recovery after TBI.

MicroRNAs (miRNAs), small non-protein-coding RNA molecules, modulate target gene expression by binding to 3′untranslated regions (UTR) of target mRNA. These molecules are aberrantly expressed in many human cancers, and can function either as tumor suppressors or oncogenes. In the current study, we show that miR-107 is down-regulated in glioma tissues and cell lines, and its overexpression leads to inhibition of the migratory and invasive ability of glioma cells via direct targeting of Notch2, which is known to transactivate Tenascin-C and Cox-2. Experiments with Notch2 siRNA further suggest that miR-107 may exerts its anti-invasive activity through Notch2 signaling pathways. Our findings collectively indicate that miR-107 is involved in glioma cell migration and invasion, and support its utility as a potential target for glioma treatment.

Glioma stem cells (GSCs) are thought to be critical for resistance to radiotherapy and chemotherapy and for tumor recurrence after surgery in glioma patients. Identification of new therapeutic strategies that can target GSCs may thus be critical for improving patient survival. MicroRNAs (miRNAs) are small non-coding RNAs that function as tumor suppressors or oncogenes. In this study, we confirmed that miR-107 was down-regulated in GSCs. To investigate the role of miR-107 in tumorigenesis of GSCs, a lentiviral vector over-expressing miR-107 in U87GSCs was constructed. We found that over-expression of miR-107 suppressed proliferation and down-regulated Notch2 protein and stem cell marker (CD133 and Nestin) expression in U87GSCs. Furthermore, enhanced miR-107 expression significantly inhibited U87GSC invasion and reduced matrix metalloproteinase-12 expression. miR-107 also suppressed U87GSCs xenograft growth in vivo. These findings suggest that miR-107 is involved in U87GSCs growth and invasion and may provide a potential therapeutic target for glioma treatment.

Objective To explore the association between transforming growth factor-beta1 (TGF-β1) T869C polymorphism and risk of ischemic stroke (IS) by performing a meta-analysis based on published articles. Methods Systematic electronic searches of PubMed, Science Direct, BIOSIS Previews, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, and WANFANG Database were performed. The strength of the association was calculated by pooled odds ratios (ORs) with 95% confidence intervals (95%CIs). Subgroup analysis was conducted to explore potential sources of heterogeneity. Sensitivity analysis was performed to elucidate the stability of the outcomes. Publication bias was evaluated by Begg’s funnel plot and Egger’s test. Results A total of 6 studies involving 1701 cases were included. The overall estimates did not show any significant association between TGF-β1 T869C polymorphism and risk of IS under all genetic models (C vs. T: OR = 1.08,95%CI = 0.88–1.32; CC vs. TT:OR = 1.17,95%CI = 0.79–1.72; CT vs. TT: OR = 0.91, 95%CI = 0.68–1.22; CC+CT vs. TT: OR = 0.99, 95%CI = 0.73–1.35; CC vs. CT+TT: OR = 1.23, 95%CI = 0.95–1.59). Similar lacking associations were observed in subgroup analysis based on ethnicity and source of controls. When stratified by study design, significant increased association of IS risk was found in cohort studies under genetic models except recessive model(C vs. T: OR = 1.18, 95%CI = 1.05–1.32; CC vs. TT: OR = 1.40, 95%CI = 1.10–1.77; CT vs. TT: OR = 1.23, 95%CI = 1.02–1.49; CC+CT vs. TT: OR = 1.27, 95%CI = 1.03–1.57; CC vs. CT+TT, OR = 1.21, 95%CI = 0.99–1.47), whereas in case-control studies a significant decreased risk was detected under heterozygote comparison(CT vs. CC: OR = 0.72, 95%CI = 0.57–0.92). However, after correction for multiple testing, the associations were observed to be null significant in both cohort and case-control subgroups among all genetic models. Conclusion This meta-analysis suggested that current epidemiological studies of TGF-β1 T869C polymorphism are too inconsistent to draw a conclusion on the association with IS susceptibility. Given the small sample size and remarkable between-study heterogeneity, further well-designed prospective large-scale studies are warranted.

Glioblastoma stem cells (GSCs) play an important role in the progression and recurrence of malignant glioblastoma because of their potential for self-renewal, multilineage differentiation and tumor initiation. A disintegrin and metalloproteinase 17 (ADAM17) is responsible for the proteolytic cleavage of Notch within its extracellular domain leading to the activation of Notch signaling, which is involved in the formation and maintenance of GSCs. Here, we show that glioma cells expressing the stem cell marker CD133 coexpress higher levels of ADAM17 than matched CD133-glioma cells. Knockdown of the ADAM17 gene in U87 GSCs down-regulated the expression of CD133, inhibited secondary neurosphere formation and induced multi-lineage differentiation. Furthermore, knockdown of ADAM17 inhibited Hes1 and Hes5 and activated Notch1 expression, which may explain the ADAM17 shRNA-induced suppression of self-renewal and differentiation of U87 GSCs. Our results suggest that ADAM17 may maintain the stemness of GSCs by promoting their self-renewal and inhibiting their differentiation via Notch signaling.

Many studies have shown that microglia in the activated state may be neurotoxic. It has been proven that uncontrolled or over-activated microglia play an important role in many neurodegenerative disorders. Bone marrow-derived mesenchymal stem cells (BMSCs) have been shown in many animal models to have a therapeutic effect on neural damage. Such a therapeutic effect is attributed to the fact that BMSCs have the ability to differentiate into neurons and to produce trophic factors, but there is little information available in the literature concerning whether BMSCs play a therapeutic role by affecting microglial activity. In this study, we triggered an inflammatory response situation in vitro by stimulating microglia with the bacterial endotoxin lipopolysaccharide (LPS), and then culturing these microglia with BMSC-conditioned medium (BMSC-CM). We found that BMSC-CM significantly inhibited proliferation and secretion of pro-inflammatory factors by activated microglia. Furthermore, we found that the phagocytic capacity of microglia was also inhibited by BMSC-CM. Finally, we investigated whether the induction of apoptosis and the production of nitric oxide (NO) were involved in the inhibition of microglial activation. We found that BMSC-CM significantly induced apoptosis of microglia, while no apoptosis was apparent in the LPS-stimulated microglia. Our study also provides evidence that NO participates in the inhibitory effect of BMSCs. Our experimental results provide evidence that BMSCs have the ability to maintain the resting phenotype of microglia or to control microglial activation through their production of several factors, indicating that BMSCs could be a promising therapeutic tool for treatment of diseases associated with microglial activation.