scholarly journals An Orchestrated Response To Tumor Signals By Macrophages and Mesenchymal Stem Cells Potentiates Interleukin-6 Secretion In Glioblastoma

2014 ◽  
Vol 1 (1) ◽  
Author(s):  
Kevin Anton ◽  
John Glod
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Cell ◽  
Tumor Progression ◽  
Interleukin 6 ◽  
Critical Role ◽  
Soluble Factors ◽  
Secreted Factors ◽  
Secretion Profile ◽  
Cytokine Secretion Profile

AbstractThe tumor microenvironment plays a critical role in the survival, growth, invasion, and metastasis of solid tumors. However, the mechanisms by which it influences these aspects of tumor progression remain incompletely characterized. In this study, we show that human glioblastoma cells secrete soluble factors that alter the phenotype and cytokine secretion profile of both macrophages and mesenchymal stem cells (MSCs). Macrophages and MSCs respond to tumor-secreted factors by increasing the release of interleukin-6 (IL-6) and this response is potentiated when macrophages and MSCs are combined in co-culture. In glioblastoma, IL-6 has been associated with tumor cell invasion, angiogenesis, tumor cell proliferation, immune suppression, and poor prognosis. Our results suggest that the orchestrated response of macrophages and stromal elements to neoplastic cells enhances tumor progression through the release of soluble factors.

scholarly journals The inflammatory signalling mediator TAK1 mediates lymphocyte recruitment to lipopolysaccharide-activated murine mesenchymal stem cells through interleukin-6

2021 ◽  
Author(s):  
Beatrice Oelze ◽  
Kirsten Elger ◽  
Patrik Schadzek ◽  
Laura Burmeister ◽  
Anika Hamm ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Interleukin 6 ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Inflammatory Signals ◽  
Secreted Factors ◽  
Anti Inflammatory ◽  
Inflammatory Signalling

AbstractAs a response to pro-inflammatory signals mesenchymal stem cells (MSCs) secrete agents and factors leading to lymphocyte recruitment, counteracting inflammation, and stimulating immunosuppression. On a molecular level, the signalling mediator TGF-β-activated kinase 1 (TAK1) is activated by many pro-inflammatory signals, plays a critical role in inflammation and regulates innate and adaptive immune responses as well. While the role of TAK1 as a signalling factor promoting inflammation is well documented, we also considered a role for TAK1 in anti-inflammatory actions exerted by activated MSCs. We, therefore, investigated the capacity of lipopolysaccharide (LPS)-treated murine MSCs with lentivirally modulated TAK1 expression levels to recruit lymphocytes. TAK1 downregulated by lentiviral vectors expressing TAK1 shRNA in murine MSCs interfered with the capacity of murine MSCs to chemoattract lymphocytes, indeed. Analysing a pool of 84 secreted factors we found that among 26 secreted cytokines/factors TAK1 regulated expression of one cytokine in LPS-activated murine MSCs in particular: interleukin-6 (IL-6). IL-6 in LPS-treated MSCs was responsible for lymphocyte recruitment as substantiated by neutralizing antibodies. Our studies, therefore, suggest that in LPS-treated murine MSCs the inflammatory signalling mediator TAK1 may exert anti-inflammatory properties via IL-6.

scholarly journals Secretion of interleukin-6 by bone marrow mesenchymal stem cells promotes metastasis in hepatocellular carcinoma

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Fei Mi ◽  
Liansheng Gong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Cell Invasion ◽  
Interleukin 6 ◽  
Critical Role ◽  
Response To Treatment ◽  
Signal Transducer ◽  
Stat3 Pathway

Mesenchymal stem cells (MSCs) interact with tumor cells and regulate tumorigenesis and metastasis. As one of the important components of the tumor microenvironment, MSC-secreted cytokines play a critical role in cancer development. However, whether and how bone marrow MSCs (BMSCs) and their secreted cytokines participate in hepatocellular carcinoma (HCC) progression, still remains largely unknown. In the present study, we first measured the concentration of interleukin-6 (IL-6) in BMSC conditioned medium (BMSC-CM). Next, we assessed the changes of invasion ability in response to treatment of BMSC-CM or recombinant IL-6 in two human HCC cell lines Bel-7404 and HepG2. Then we analyzed the level of key components of the IL-6 signal pathway, including IL-6 receptor and signal transducer (i.e. IL-6R and gp130), a transcription factor STAT3 (signal transducer and activator of transcription 3), as well as its target genes BCL2, CCND1, MCL1 and MMP2, in BMSC-CM or recombinant IL-6 treated Bel-7404 and HepG2 cells. Results showed that a considerable amount of IL-6 was secreted by BMSCs, and BMSC-CM markedly elevated Bel-7404 cell invasion rate and stimulated the signal transduction of IL-6/STAT3 pathway. Neutralizing the secreted IL-6 bioactivity by the anti-IL-6 antibody diminished the invasion-promoting effect and down-regulated IL-6/STAT3 pathway of BMSC-CM treated Bel-7404 cells. In conclusion, we found that BMSCs may activate the IL-6/STAT3 signaling pathway and promote cell invasion in Bel-7404 cells, suggesting that this protumor effect should be seriously considered before clinical application of MSC-mediated cancer therapy.

scholarly journals Helicobacter pylori Infection-Induced Hepatoma-Derived Growth Factor Regulates the Differentiation of Human Mesenchymal Stem Cells to Myofibroblast-Like Cells

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 479 ◽  
Author(s):  
Chung-Jung Liu ◽  
Yao-Kuang Wang ◽  
Fu-Chen Kuo ◽  
Wen-Hung Hsu ◽  
Fang-Jung Yu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stem Cells ◽  
Helicobacter Pylori ◽  
Mesenchymal Stem Cells ◽  
Growth Factor ◽  
Tumor Cell ◽  
Critical Role ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
H Pylori

Hepatoma-derived growth factor (HDGF) plays a critical role in tumor cell proliferation, anti-apoptosis, VEGF expression, lymph node metastasis and poor prognosis in human gastric cancer. Gastric cancer, as one of the most prevalent cancers worldwide, is the second leading cause of cancer-related mortality in the world for the prognosis of gastric cancer is generally poor, especially in patients with advanced stage. Helicobacter pylori (H. pylori) infection causes the chronic inflammation of stomach as well as the development of gastric cancer, with a three to six-fold increased risk of gastric cancer. Carcinoma-associated fibroblasts (CAFs) are myofibroblasts in tumor microenvironment, which possess various abilities to promote the progression of cancer by stimulating neoangiogenesis, proliferation, migration, invasion and therapy resistance of tumor cell. Mesenchymal stem cells (MSCs) are reported to promote tumor malignance through differentiation of MSCs toward CAFs. In the present study, we demonstrated that H. pylori infection promotes HDGF expression in human gastric cancer cells. HBMMSCs treated with HDGF assume properties of CAF-like myofibroblastic phenotypes, including expression of myofibroblast markers (α-smooth muscle actin (α-SMA), procollagen α1, tropomyoson I, desmin, fibroblast activation protein (FAP)), and fibroblast markers (prolyl-4-hydroxylase A1 (PHA1) and fibroblast specific protein-1 (FSP-1)/S100A4). HDGF recruits HBMMSCs, and then HBMMSCs further contributes to cell survival and invasive motility in human gastric cancer cells. Treatment of HDGF neutralizing antibody (HDGF-NAb) and serum significantly inhibit HDGF-regulated differentiation and recruitment of HBMMSCs. These findings suggest that HDGF might play a critical role in gastric cancer progress through stimulation of HBMMSCs differentiation to myofibroblast-like cells.

Microwell Geometry Modulates Interleukin-6 Secretion in Human Mesenchymal Stem Cells

MRS Advances ◽  
2017 ◽  
Vol 2 (47) ◽  
pp. 2561-2570
Author(s):  
Xun Xu ◽  
Weiwei Wang ◽  
Zhengdong Li ◽  
Karl Kratz ◽  
Nan Ma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Interleukin 6 ◽  
Therapeutic Potential ◽  
Chemical Properties ◽  
Human Mesenchymal Stem Cells ◽  
Secretion Profile ◽  
Highly Sensitive ◽  
Physical And Chemical ◽  
Cell Culture Substrate

ABSTRACTThe therapeutic effect of mesenchymal stem cells (MSCs) has been investigated in various clinical applications, in which their functional benefits are mainly attributed to the secretion of soluble factors. The enhancement of their therapeutic potential by physical and chemical properties of cell culture substrate is a safe and effective strategy, since they are highly sensitive to their microenvironment such as the elasticity and surface topography. In this study, we demonstrated that the geometry of polymeric substrate regulated the interleukin-6 (IL-6) secretion of human adipose derived MSCs. Polystyrene substrates comprising arrays of square-shaped (S50) or round-shaped (R50) microwells (side length or diameter of 50 μm and depth of 10 μm) were prepared by injection molding. Cellular apoptototic rate of MSCs was not affected by the microwell geometry, while the upregulated secretion of IL-6 and the enhancement of nuclear transcription factor STAT3 were detected in MSCs seeded on S50 substrate. The geometry-dependent modulatory effect was highly associated with ROCK signaling cascade. The inhibition of ROCK abolished the disparity in IL-6 secretion. These findings highlight the possibility to steer the secretion profile of stem cells via microwell geometry in combination with the manipulation of ROCK signaling pathway.

scholarly journals Mesenchymal Stem Cells Derived from Adipose Accelerate the Progression of Colon Cancer by Inducing a MT-CAFs Phenotype via TRPC3/NF-KB Axis

2021 ◽  
Author(s):  
Chunling Xue ◽  
Yang Gao ◽  
Xuechun Li ◽  
Mingjia Zhang ◽  
Ying Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Colon Cancer ◽  
Mesenchymal Stem Cells ◽  
Ion Channel ◽  
Tumor Progression ◽  
Signaling Pathway ◽  
Calcium Influx ◽  
Critical Role ◽  
Migration And Invasion ◽  
Channel Protein

Abstract Background: There is increasing evidence that mesenchymal stem cells (MSCs) help shape the tumor microenvironment and promote tumor progression, and ion channels might play a critical role in this process. Methods: Gene chip was used for a general analysis of gene expression changes in MSC-transformed CAF cells (MT-CAFs). We screened out the ion channel protein TRPC3 with WB detecion and lentivirus knockdown. Calcium influx was detected by two-photon microscope. MTS and Transwell detected growth, migration, and invasion of MT-CAFs and HCT116 cells. Bioinformatic tools and clinical specimens were to assess the relationship between TRPC3 and surrvival.Results: We screened out the ion channel protein TRPC3 with significantly increased expression, which caused calcium influx, and further activated the NF-KB signaling pathway. Knockdown or inhibition of TRPC3 in MSCs significantly reduced the activation of NF-KB, and decreased the growth, migration, and invasion of MT-CAFs. After TRPC3 knockdown, the ability of MT- CAFs to promote tumor migration and invasion was impaired. Conversely, the upregulation of TRPC3 expression in MT-CAFs had the opposite effect. In vivo, TRPC3 expressed on MSCs also contributed to the tumorigenesis and progression of cancer cells. In addition, the Oncomine and GEPIA databases showed that TRPC3 expression is higher in colon cancer tissue compared with normal colon tissues, and is positively correlated with the expression of the CAF genes alpha-smooth muscle (α-SMA/ACTA2) and fibroblast activation protein Alpha (FAP). The disease-free survival of patients with positive TRPC3 expression in mesenchymal cells was significantly shorter than in those with negative expression. Conclusions: These results indicate that TRPC3 expressed on MT-CAFs plays a critical role in tumor progression via the NF-KB signaling pathway, and is correlated with poor prognosis in colon cancer patients. Therefore, TRPC3 may be a novel therapeutic target for the treatment of colon cancer.

Overexpression of Pygo2 Increases Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Cardiomyocyte-like Cells

2020 ◽  
Vol 20 (4) ◽  
pp. 318-324 ◽  
Author(s):  
Lei Yang ◽  
Shuoji Zhu ◽  
Yongqing Li ◽  
Jian Zhuang ◽  
Jimei Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Heart Function ◽  
Critical Role ◽  
Human Umbilical Cord ◽  
Stem Cell Markers ◽  
Quantitative Real Time Pcr ◽  
Qrt Pcr

Background: Our previous studies have shown that Pygo (Pygopus) in Drosophila plays a critical role in adult heart function that is likely conserved in mammals. However, its role in the differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into cardiomyocytes remains unknown. Objective: To investigate the role of pygo2 in the differentiation of hUC-MSCs into cardiomyocytes. Methods: Third passage hUC-MSCs were divided into two groups: a p+ group infected with the GV492-pygo2 virus and a p− group infected with the GV492 virus. After infection and 3 or 21 days of incubation, Quantitative real-time PCR (qRT-PCR) was performed to detect pluripotency markers, including OCT-4 and SOX2. Nkx2.5, Gata-4 and cTnT were detected by immunofluorescence at 7, 14 and 21 days post-infection, respectively. Expression of cardiac-related genes—including Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin—were analyzed by qRT-PCR following transfection with the virus at one, two and three weeks. Results : After three days of incubation, there were no significant changes in the expression of the pluripotency stem cell markers OCT-4 and SOX2 in the p+ group hUC-MSCs relative to controls (OCT-4: 1.03 ± 0.096 VS 1, P > 0.05, SOX2: 1.071 ± 0.189 VS 1, P > 0.05); however, after 21 days, significant decreases were observed (OCT-4: 0.164 ± 0.098 VS 1, P < 0.01, SOX2: 0.209 ± 0.109 VS 1, P < 0.001). Seven days following incubation, expression of mesoderm specialisation markers, such as Nkx2.5, Gata-4, MEF2c and KDR, were increased; at 14 days following incubation, expression of cardiac genes, such as Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin, were significantly upregulated in the p+ group relative to the p− group (P < 0.05). Taken together, these findings suggest that overexpression of pygo2 results in more hUCMSCs gradually differentiating into cardiomyocyte-like cells. Conclusion: We are the first to show that overexpression of pygo2 significantly enhances the expression of cardiac-genic genes, including Nkx2.5 and Gata-4, and promotes the differentiation of hUC-MSCs into cardiomyocyte-like cells.

scholarly journals Pre-Exposure of Human Adipose Mesenchymal Stem Cells to Soluble Factors Enhances Their Homing to Brain Cancer

2015 ◽  
Vol 4 (3) ◽  
pp. 239-251 ◽  
Author(s):  
Chris L. Smith ◽  
Kaisorn L. Chaichana ◽  
Young M. Lee ◽  
Benjamin Lin ◽  
Kevin M. Stanko ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Brain Cancer ◽  
Soluble Factors ◽  
Adipose Mesenchymal Stem Cells

scholarly journals Cyclic Mechanical Strain Regulates Osteoblastic Differentiation of Mesenchymal Stem Cells on TiO2 Nanotubes Through GCN5 and Wnt/β-Catenin

2021 ◽  
Vol 9 ◽  
Author(s):  
Yanchang Liu ◽  
Wendan Cheng ◽  
Yao Zhao ◽  
Liang Gao ◽  
Yongyun Chang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Differentiation ◽  
Mechanical Stress ◽  
Critical Role ◽  
Mechanical Strain ◽  
Biological Behavior ◽  
Mechanical Stimuli ◽  
Mechanical Signals ◽  
Alkaline Phosphatase Staining

Bone marrow mesenchymal stem cells (BMSCs) play a critical role in bone formation and are extremely sensitive to external mechanical stimuli. Mechanical signals can regulate the biological behavior of cells on the surface of titanium-related prostheses and inducing osteogenic differentiation of BMSCs, which provides the integration of host bone and prosthesis benefits. But the mechanism is still unclear. In this study, BMSCs planted on the surface of TiO2 nanotubes were subjected to cyclic mechanical stress, and the related mechanisms were explored. The results of alkaline phosphatase staining, real-time PCR, and Western blot showed that cyclic mechanical stress can regulate the expression level of osteogenic differentiation markers in BMSCs on the surface of TiO2 nanotubes through Wnt/β-catenin. As an important member of the histone acetyltransferase family, GCN5 exerted regulatory effects on receiving mechanical signals. The results of the ChIP assay indicated that GCN5 could activate the Wnt promoter region. Hence, we concluded that the osteogenic differentiation ability of BMSCs on the surface of TiO2 nanotubes was enhanced under the stimulation of cyclic mechanical stress, and GCN5 mediated this process through Wnt/β-catenin.

scholarly journals Positively Correlated CD47 Activation and Autophagy in Umbilical Cord Blood-Derived Mesenchymal Stem Cells during Senescence

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Gee-Hye Kim ◽  
Yun Kyung Bae ◽  
Ji Hye Kwon ◽  
Miyeon Kim ◽  
Soo Jin Choi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Growth ◽  
Cell Therapy ◽  
Critical Role ◽  
Therapeutic Effects ◽  
Stem Cell Maintenance ◽  
Selection Of

Autophagy plays a critical role in stem cell maintenance and is related to cell growth and cellular senescence. It is important to find a quality-control marker for predicting senescent cells. This study verified that CD47 could be a candidate to select efficient mesenchymal stem cells (MSCs) to enhance the therapeutic effects of stem cell therapy by analyzing the antibody surface array. CD47 expression was significantly decreased during the expansion of MSCs in vitro ( p < 0.01 ), with decreased CD47 expression correlated with accelerated senescence phenotype, which affected cell growth. UCB-MSCs transfected with CD47 siRNA significantly triggered the downregulation of pRB and upregulation of pp38, which are senescence-related markers. Additionally, autophagy-related markers, ATG5, ATG12, Beclin1, and LC3B, revealed significant downregulation with CD47 siRNA transfection. Furthermore, autophagy flux following treatment with an autophagy inducer, rapamycin, has shown that CD47 is a key player in autophagy and senescence to maintain and regulate the growth of MSCs, suggesting that CD47 may be a critical key marker for the selection of effective stem cells in cell therapy.

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