scholarly journals The DLC-1 tumor suppressor is involved in regulating immunomodulation of human mesenchymal stem cells through interacting with the Notch1 protein

2020 ◽  
Author(s):  
Tao Na ◽  
Kehua Zhang ◽  
Bao-Zhu Yuan
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Suppressor ◽  
Protein Degradation ◽  
Signaling Pathway ◽  
Mutual Exclusion ◽  
Human Mesenchymal Stem Cells ◽  
Fine Tuning ◽  
Notch1 Signaling ◽  
Immunomodulatory Function

Abstract Background Immunomodulatory activities of human mesenchymal stem cells (hMSCs) has been widely recognized as the most critical function of hMSCs for exerting its therapeutic effects. However, the detailed mechanisms responsible for regulating the immunomodulation of hMSCs still remain largely unknown. Previous studies revealed that the Notch1 protein exerted a pro-immunomodulatory function probably through interacting with the protein(s) subjective to proteasome-mediated protein degradation. The DLC-1 protein represents a well characterized tumor suppressor subjective to proteasome-mediated degradation. However, the detailed signaling pathway of Notch1 and the involvement of DLC-1 in regulating the immunomodulation of hMSCs have not been studied before. Methods The transfection with cDNA or siRNA into hMSCs assisted by co-culture of hMSCs with peripheral blood mononuclear cells and small molecule inhibitors of signaling proteins, followed by immunoprecipitation, Western blotting, RT-PCR, and flowcytometry, were employed to characterize the Notch1 signaling, to identify DLC-1 as a candidate proteasome-targeted protein, and to characterize DLC-1 signaling pathway and its interaction with the Notch1 signaling, in the regulation of immunomodulation of hMSCs, specifically, the inhibition of pro-inflammatory CD4+-Th1 lymphocytes, and the release of immunomodulatory molecule IDO1. Statistical analysis One-way ANOVA was utilized as a statistical tool to analyze the data presented as means ± SEM of at least three separate experiments. Results The present study revealed that the Notch1-Hey1 axis, but not the Notch1-Hes1 axis, was likely responsible for mediating the pro-immunomodulatory function of the Notch1 signaling. The DLC-1 protein was found subjective to proteasome-mediated protein degradation mediated by the DDB1 and FBXW5 E3 ligases and served as an inhibitor of the immunomodulation of hMSCs through inhibiting Rock1, but not Rock2, downstream the DLC-1 signaling. The Notch1 signaling in the Notch1-Hey1 pathway and the DLC-1 signaling in the DLC-1-Rock1-FBXW5 pathway exhibited a mutual exclusion interaction in the regulation of immunomodulation of hMSCs. Conclusions The present study uncovers a novel function of DLC-1 tumor suppressor in regulating the immunomodulation of hMSCs. It also proposes a novel mutual exclusion mechanism between the DLC-1 signaling and the Notch1 signaling that is possibly responsible for fine-tuning the immunomodulation of hMSCs with different clinical implications in hMSCs therapy.

scholarly journals The DLC-1 tumor suppressor is involved in regulating immunomodulation of human mesenchymal stromal /stem cells through interacting with the Notch1 protein

2020 ◽  
Author(s):  
Tao Na ◽  
Kehua Zhang ◽  
Bao-Zhu Yuan
Keyword(s):  
Stem Cells ◽  
Tumor Suppressor ◽  
Protein Degradation ◽  
Signaling Pathway ◽  
Mutual Exclusion ◽  
Fine Tuning ◽  
Therapeutic Effects ◽  
Notch1 Signaling ◽  
Stromal Stem Cells ◽  
Immunomodulatory Function

Abstract BackgroundImmunomodulatory activities of human mesenchymal stromal /stem cells (hMSCs) has been widely recognized as the most critical function of hMSCs for exerting its therapeutic effects. However, the detailed mechanisms responsible for regulating the immunomodulation of hMSCs still remain largely unknown. Previous studies revealed that the Notch1 protein exerted a pro-immunomodulatory function probably through interacting with the protein(s) subjective to proteasome-mediated protein degradation. The DLC-1 protein represents a well characterized tumor suppressor subjective to proteasome-mediated degradation. However, the detailed signaling pathway of Notch1 and the involvement of DLC-1 in regulating the immunomodulation of hMSCs have not been studied before.MethodsThe transfection with cDNA or siRNA into hMSCs assisted by co-culture of hMSCs with peripheral blood mononuclear cells and small molecule inhibitors of signaling proteins, followed by immunoprecipitation, Western blotting, RT-PCR, and flowcytometry, were employed to characterize the Notch1 signaling, to identify DLC-1 as a candidate proteasome-targeted protein, and to characterize DLC-1 signaling pathway and its interaction with the Notch1 signaling, in the regulation of immunomodulation of hMSCs, specifically, the inhibition of pro-inflammatory CD4+-Th1 lymphocytes, and the release of immunomodulatory molecule IDO1.Statistical analysisOne-way ANOVA was utilized as a statistical tool to analyze the data presented as means ± SEM of at least three separate experiments.ResultsThe present study revealed that the Notch1-Hey1 axis, but not the Notch1-Hes1 axis, was likely responsible for mediating the pro-immunomodulatory function of the Notch1 signaling. The DLC-1 protein was found subjective to proteasome-mediated protein degradation mediated by the DDB1 and FBXW5 E3 ligases and served as an inhibitor of the immunomodulation of hMSCs through inhibiting Rock1, but not Rock2, downstream the DLC-1 signaling. The Notch1 signaling in the Notch1-Hey1 pathway and the DLC-1 signaling in the DLC-1-Rock1-FBXW5 pathway exhibited a mutual exclusion interaction in the regulation of immunomodulation of hMSCs.ConclusionsThe present study uncovers a novel function of DLC-1 tumor suppressor in regulating the immunomodulation of hMSCs. It also proposes a novel mutual exclusion mechanism between the DLC-1 signaling and the Notch1 signaling that is possibly responsible for fine-tuning the immunomodulation of hMSCs with different clinical implications in hMSCs therapy.

scholarly journals The DLC-1 tumor suppressor is involved in regulating immunomodulation of human mesenchymal stromal /stem cells through interacting with the Notch1 protein

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Tao Na ◽  
Kehua Zhang ◽  
Bao-Zhu Yuan
Keyword(s):  
Stem Cells ◽  
Tumor Suppressor ◽  
Protein Degradation ◽  
Signaling Pathway ◽  
Mutual Exclusion ◽  
Fine Tuning ◽  
Therapeutic Effects ◽  
Notch1 Signaling ◽  
Stromal Stem Cells ◽  
Immunomodulatory Function

Abstract Background Immunomodulatory activities of human mesenchymal stromal /stem cells (hMSCs) has been widely recognized as the most critical function of hMSCs for exerting its therapeutic effects. However, the detailed mechanisms responsible for regulating the immunomodulation of hMSCs still remain largely unknown. Previous studies revealed that the Notch1 protein exerted a pro-immunomodulatory function probably through interacting with the protein(s) subjective to proteasome-mediated protein degradation. The DLC-1 protein represents a well characterized tumor suppressor subjective to proteasome-mediated degradation. However, the detailed signaling pathway of Notch1 and the involvement of DLC-1 in regulating the immunomodulation of hMSCs have not been studied before. Methods The transfection with cDNA or siRNA into hMSCs assisted by co-culture of hMSCs with peripheral blood mononuclear cells and small molecule inhibitors of signaling proteins, followed by immunoprecipitation, Western blotting, RT-PCR, and flowcytometry, were employed to characterize the Notch1 signaling, to identify DLC-1 as a candidate proteasome-targeted protein, and to characterize DLC-1 signaling pathway and its interaction with the Notch1 signaling, in the regulation of immunomodulation of hMSCs, specifically, the inhibition of pro-inflammatory CD4+-Th1 lymphocytes, and the release of immunomodulatory molecule IDO1. Statistical analysis One-way ANOVA was utilized as a statistical tool to analyze the data presented as means ± SEM of at least three separate experiments. Results The present study revealed that the Notch1-Hey1 axis, but not the Notch1-Hes1 axis, was likely responsible for mediating the pro-immunomodulatory function of the Notch1 signaling. The DLC-1 protein was found subjective to proteasome-mediated protein degradation mediated by the DDB1 and FBXW5 E3 ligases and served as an inhibitor of the immunomodulation of hMSCs through inhibiting Rock1, but not Rock2, downstream the DLC-1 signaling. The Notch1 signaling in the Notch1-Hey1 pathway and the DLC-1 signaling in the DLC-1-Rock1-FBXW5 pathway exhibited a mutual exclusion interaction in the regulation of immunomodulation of hMSCs. Conclusions The present study uncovers a novel function of DLC-1 tumor suppressor in regulating the immunomodulation of hMSCs. It also proposes a novel mutual exclusion mechanism between the DLC-1 signaling and the Notch1 signaling that is possibly responsible for fine-tuning the immunomodulation of hMSCs with different clinical implications in hMSCs therapy.

scholarly journals The DLC-1 tumor suppressor is involved in regulating immunomodulation of human mesenchymal stem cells through interacting with the Notch1 protein

2019 ◽  
Author(s):  
Tao Na ◽  
Kehua Zhang ◽  
Bao-Zhu Yuan
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Suppressor ◽  
Mutual Exclusion ◽  
Human Mesenchymal Stem Cells ◽  
Fine Tuning ◽  
Therapeutic Effects ◽  
Critical Function ◽  
E3 Ligases ◽  
Notch1 Signaling

Abstract Immunomodulatory activities of human mesenchymal stem cells (hMSCs) have been widely accepted as the most critical function of the cells for exerting its therapeutic effects. The activities include the inhibition by hMSCs on pro-inflammatory CD4 + -T lymphocytes, and the release of immunomodulatory molecules, like IDO1. However, the detailed mechanisms responsible for regulating the immunomodulation of hMSCs still remain largely unknown. Previously, the Notch1 protein has been demonstrated to be able to promote the immunomodulation of hMSCs through inhibiting CD4 + -Th1 lymphocyte proliferation and enhancing IDO1 expression. The present study further revealed that it was the Notch1-Hey1 axis, rather than the Notch1-Hes1 axis, that was likely responsible for mediating the immunomodulation of the Notch1 signaling. Meanwhile, following a previously proposed hypothesis to identify proteasome-regulated protein(s) for limiting the activity of the Notch1 signaling in hMSCS, the DLC-1 tumor suppressor was identified to be such a candidate protein, which was subjected to protein degradation mediated by the DDB1 and FBXW5 E3 ligases . It was further shown that the DLC-1 signaling composing of DLC-1, Rock1 and FBXW5 proteins was involved in inhibiting the immunomodulation of hMSCs. More importantly, the immunomodulation was achieved through an interaction between the DLC-1-FBXW5-Rock1 signaling and the Notch1-Hey1 signaling . In fact, the present study a novel function of DLC-1 tumor suppressor as well as proposed a new mutual exclusion mechanism likely responsible for fine-tuning the immunomodulation of hMSCs.

scholarly journals The DLC-1 tumor suppressor is involved in regulating immunomodulation of human mesenchymal stem/stromal cells through interacting with the Notch1 protein

2020 ◽  
Author(s):  
Tao Na ◽  
Kehua Zhang ◽  
Bao-Zhu Yuan
Keyword(s):  
Tumor Suppressor ◽  
Protein Degradation ◽  
Signaling Pathway ◽  
Stromal Cells ◽  
Mutual Exclusion ◽  
Fine Tuning ◽  
Therapeutic Effects ◽  
E3 Ligases ◽  
Notch1 Signaling ◽  
Immunomodulatory Function

Abstract Background Immunomodulatory activities of human mesenchymal stem/stromal cells (hMSCs) has been widely recognized as the most critical function of hMSCs for exerting its therapeutic effects. However, the detailed mechanisms responsible for regulating the immunomodulation of hMSCs still remain largely unknown. Previous studies revealed that the Notch1 protein exerted a pro-immunomodulatory function probably through interacting with the protein(s) subjective to proteasome-mediated protein degradation. The DLC-1 protein represents a well characterized tumor suppressor subjective to proteasome-mediated degradation. However, the detailed signaling pathway of Notch1 and the involvement of DLC-1 in regulating the immunomodulation of hMSCs have not been studied before. Methods The transfection with cDNA or siRNA into hMSCs assisted by co-culture of hMSCs with peripheral blood mononuclear cells and small molecule inhibitors of signaling proteins, followed by immunoprecipitation, Western blotting, RT-PCR, and flowcytometry, were employed to characterize the Notch1 signaling, to identify DLC-1 as a candidate proteasome-targeted protein, and to characterize DLC-1 signaling pathway and its interaction with the Notch1 signaling, in the regulation of immunomodulation of hMSCs, specifically, the inhibition of pro-inflammatory CD4 + -Th1 lymphocytes, and the release of immunomodulatory molecule IDO1. Statistical analysis One-way ANOVA was utilized as a statistical tool to analyze the data presented as means ± SEM of at least three separate experiments. Results The present study revealed that the Notch1-Hey1 axis, but not the Notch1-Hes1 axis, was likely responsible for mediating the pro-immunomodulatory function of the Notch1 signaling. The DLC-1 protein was found subjective to proteasome-mediated protein degradation mediated by the DDB1 and FBXW5 E3 ligases and served as an inhibitor of the immunomodulation of hMSCs through inhibiting Rock1, but not Rock2, downstream the DLC-1 signaling. The Notch1 signaling in the Notch1-Hey1 pathway and the DLC-1 signaling in the DLC-1-Rock1-FBXW5 pathway exhibited a mutual exclusion interaction in the regulation of immunomodulation of hMSCs. Conclusions The present study uncovers a novel function of DLC-1 tumor suppressor in regulating the immunomodulation of hMSCs. It also proposes a novel mutual exclusion mechanism between the DLC-1 signaling and the Notch1 signaling that is possibly responsible for fine-tuning the immunomodulation of hMSCs with different clinical implications in hMSCs therapy.

TNFα promotes osteogenic differentiation of human mesenchymal stem cells by triggering the NF-κB signaling pathway

Bone ◽  
2009 ◽  
Vol 45 (2) ◽  
pp. 367-376 ◽  
Author(s):  
Katrin Hess ◽  
Alexey Ushmorov ◽  
Jörg Fiedler ◽  
Rolf E. Brenner ◽  
Thomas Wirth
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Differentiation ◽  
Signaling Pathway ◽  
Human Mesenchymal Stem Cells

scholarly journals Transcriptome Profiling of IL-17A Preactivated Mesenchymal Stem Cells: A Comparative Study to Unmodified and IFN-γModified Mesenchymal Stem Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Kisha Nandini Sivanathan ◽  
Darling Rojas-Canales ◽  
Shane T. Grey ◽  
Stan Gronthos ◽  
Patrick T. Coates
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Antigen Processing ◽  
Cellular Therapy ◽  
Human Mesenchymal Stem Cells ◽  
Humoral Response ◽  
Transcriptome Profiling ◽  
Antigen Processing And Presentation ◽  
Immunomodulatory Function

Human mesenchymal stem cells pretreatment with IL-17A (MSC-17) potently enhances T cell immunosuppression but not their immunogenicity, in addition to avidly promoting the induction of suppressive regulatory T cells. The aim of this study was to identify potential mechanisms by which human MSC-17 mediate their superior immunomodulatory function. Untreated-MSC (UT-MSC), IFN-γtreated MSC (MSC-γ), and MSC-17 were assessed for their gene expression profile by microarray. Significantly regulated genes were identified for their biological functions (Database for Annotation, Visualisation and Integrated Discovery, DAVID). Microarray analyses identified 1278 differentially regulated genes between MSC-γand UT-MSC and 67 genes between MSC-17 and UT-MSC. MSC-γwere enriched for genes involved in immune response, antigen processing and presentation, humoral response, and complement activation, consistent with increased MSC-γimmunogenicity. MSC-17 genes were associated with chemotaxis response, which may be involved in T cell recruitment for MSC-17 immunosuppression. MMP1, MMP13, and CXCL6 were highly and specifically expressed in MSC-17, which was further validated by real-time PCR. Thus, MMPs and chemokines may play a key role in mediating MSC-17 superior immunomodulatory function. MSC-17 represent a potential cellular therapy to suppress immunological T cell responses mediated by expression of an array of immunoregulatory molecules.

Flavonoids of Herba Epimedii regulate osteogenesis of human mesenchymal stem cells through BMP and Wnt/β-catenin signaling pathway

2010 ◽  
Vol 314 (1) ◽  
pp. 70-74 ◽  
Author(s):  
Jin-fang Zhang ◽  
Guo Li ◽  
Chu-yan Chan ◽  
Chun-ling Meng ◽  
Marie Chia-mi Lin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Signaling Pathway ◽  
Human Mesenchymal Stem Cells ◽  
Herba Epimedii

scholarly journals Quantification of Chlorogenic Acid and Vanillin from Coffee Peel Extract and its Effect on α-Amylase Activity, Immunoregulation, Mitochondrial Oxidative Stress, and Tumor Suppressor Gene Expression Levels in H2O2-Induced Human Mesenchymal Stem Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Heba Khalil Alyahya ◽  
Pandurangan Subash-Babu ◽  
Ahmad Mohammad Salamatullah ◽  
Khizar Hayat ◽  
Nawal Albader ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Suppressor ◽  
Chlorogenic Acid ◽  
Tumor Suppressor Genes ◽  
Human Mesenchymal Stem Cells ◽  
Total Polyphenol ◽  
Suppressor Genes ◽  
Mitochondrial Oxidative Stress

Background: Polyphenols and flavonoid-rich foods help in arresting reactive oxygen species development and protecting DNA from oxidative damage. Coffee peel (CP) preparations are consumed as beverages, and their total polyphenol or flavonoid content and their effect on oxidative stress–induced human mesenchymal stem cells (hMSCs) are poorly understood.Method: We prepared hot water extracts of CP (CPE) and quantified the amount of total polyphenol and flavonoid using HPLC analysis. In addition, CPE have been studied for their α-amylase inhibitory effect and beneficial effects in oxidative stress–induced hMSCs.Results: The obtained results show that the availability of chlorogenic acid, vanillin, and salicylic acid levels in CPE is more favorable for enhancing cell growth, nuclear integrity, and mitochondrial efficiency which is confirmed by propidium iodide staining and JC-1 staining. CPE treatment to hMSCs for 48 h reduced oxidative stress by decreasing mRNA expression levels of LPO and NOX-4 and in increasing antioxidant CYP1A, GSH, GSK-3β, and GPX mRNA expressions. Decreased pro-inflammatory (TNF-α, NF-κβ, IL-1β, TLR-4) and increased tumor suppressor genes (except Bcl-2) such as Cdkn2A, p53 expressions have been observed.Conclusions: The availability of CGA in CPs effectively reduced mitochondrial oxidative stress, reduced pro-inflammatory cytokines, and increased tumor suppressor genes.

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