scholarly journals Interaction with Mesenchymal Stem Cells Provokes Natural Killer Cells for Enhanced IL-12/IL-18-Induced Interferon-Gamma Secretion

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Heike Thomas ◽  
Marcus Jäger ◽  
Katharina Mauel ◽  
Sven Brandau ◽  
Sara Lask ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tissue Regeneration ◽  
Tissue Injury ◽  
Cell Contact ◽  
Dependent Manner ◽  
Close Proximity ◽  
Dose Dependent

Tissue injury induces an inflammatory response accompanied by the recruitment of immune cells and of mesenchymal stem cells (MSC) that contribute to tissue regeneration. After stimulation with interleukin- (IL-) 12 and IL-18 natural killer (NK) cells secrete the proinflammatory cytokine interferon- (IFN-)γ. IFN-γplays a crucial role in the defense against infections and modulates tissue regeneration. In consideration of close proximity of NK cells and MSC at the site of injury we investigated if MSC could influence the ability of NK-cells to produce IFN-γ. Coculture experiments were performed with bone marrow-derived human MSC and human NK cells. MSC enhanced the ability of IL-12/IL-18-stimulated NK cells to secrete IFN-γin a dose-dependent manner. This activation of NK cells was dependent on cell-cell contact as well as on soluble factors. The increased IFN-γsecretion from NK cells after contact with MSC correlated with an increased level of intracellular IFN-γ. Alterations in the IL-12 signaling pathway including an increased expression of the IL-12β1 receptor subunit and an increased phosphorylation of signal transducer and activator of transcription 4 (STAT4) could be observed. In conclusion, MSC enhance the IFN-γrelease from NK cells which might improve the defense against infections at the site of injury but additionally might affect tissue regeneration.

scholarly journals Ionizing radiation augments glioma tropism of mesenchymal stem cells

2018 ◽  
Vol 128 (1) ◽  
pp. 287-295 ◽  
Author(s):  
Jonathan G. Thomas ◽  
Brittany C. Parker Kerrigan ◽  
Anwar Hossain ◽  
Joy Gumin ◽  
Naoki Shinojima ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Ionizing Radiation ◽  
Nude Mice ◽  
Tissue Injury ◽  
Statistical Significance ◽  
Dependent Manner ◽  
Weak Attractor ◽  
Dose Dependent

OBJECTIVEMesenchymal stem cells (MSCs) have been shown to localize to gliomas after intravascular delivery. Because these cells home to areas of tissue injury, the authors hypothesized that the administration of ionizing radiation (IR) to tumor would enhance the tropism of MSCs to gliomas. Additionally, they sought to identify which radiation-induced factors might attract MSCs.METHODSTo assess the effect of IR on MSC migration in vitro, transwell assays using conditioned medium (CM) from an irradiated commercially available glioma cell line (U87) and from irradiated patient-derived glioma stem-like cells (GSCs; GSC7-2 and GSC11) were employed. For in vivo testing, green fluorescent protein (GFP)-labeled MSCs were injected into the carotid artery of nude mice harboring orthotopic U87, GSC7-2, or GSC17 xenografts that were treated with either 0 or 10 Gy of IR, and brain sections were quantitatively analyzed by immunofluorescence for GFP-positive cells. These GSCs were used because GSC7-2 is a weak attractor of MSCs at baseline, whereas GSC17 is a strong attractor. To determine the factors implicated in IR-induced tropism, CM from irradiated GSC7-2 and from GSC11 was assayed with a cytokine array and quantitative ELISA.RESULTSTranswell migration assays revealed statistically significant enhanced MSC migration to CM from irradiated U87, GSC7-2, and GSC11 compared with nonirradiated controls and in a dose-dependent manner. After their intravascular delivery into nude mice harboring orthotopic gliomas, MSCs engrafted more successfully in irradiated U87 (p = 0.036), compared with nonirradiated controls. IR also significantly increased the tropism of MSCs to GSC7-2 xenografts (p = 0.043), which are known to attract MSCs only poorly at baseline (weak-attractor GSCs). Ionizing radiation also increased the engraftment of MSCs in strong-attractor GSC17 xenografts, but these increases did not reach statistical significance. The chemokine CCL2 was released by GSC7-2 and GSC11 after irradiation in a dose-dependent manner and mediated in vitro transwell migration of MSCs. Immunohistochemistry revealed increased CCL2 in irradiated GSC7-2 gliomas near the site of MSC engraftment.CONCLUSIONSAdministering IR to gliomas enhances MSC localization, particularly in GSCs that attract MSCs poorly at baseline. The chemokine CCL2 appears to play a crucial role in the IR-induced tropism of MSCs to gliomas.

Comparison of Effects of Curcumin and Nano-curcumin on the Survival of Human-Derived Mesenchymal Stem Cells: An Experimental Study

2020 ◽  
Vol 11 (2) ◽  
pp. 148-155
Author(s):  
Pinjari Hameeda ◽  
Sandeep Katti ◽  
Rajkishore Jammalamadugu ◽  
Kishore Bhatt ◽  
Malleswara Rao Peram ◽  
...  
Keyword(s):  
Stem Cells ◽  
Experimental Study ◽  
Mesenchymal Stem Cells ◽  
Survival Rate ◽  
Cell Viability ◽  
Cell Survival ◽  
Dependent Manner ◽  
Cell Survival Rate ◽  
Post Hoc ◽  
Dose Dependent

Aim: To evaluate and compare the effect of curcumin (CUR) and Nano-curcumin (N-CUR) on human-derived mesenchymal stem cells (MSCs) in a dose-dependent manner. Materials and Methods: An experimental study performed with putative MSCs from a total of five systemically healthy subjects with chronic periodontitis. These putative MSCs were isolated by cell culture and were further characterized and identified by colony-forming unit assay and immunocytochemical analysis using cell surface markers CD105, CD146, CD45 and CD73. The identified MSCs were treated with different doses of CUR and N-CUR, and compared with α-minimum essential medium (α -MEM) for its cell viability by performing MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay for 48 and 72 hr. The statistically analysis was performed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test and Bonferroni’s post hoc test. Results: Compared to the α-MEM group, both CUR and N-CUR treated cells have shown significantly ( P = .029) higher survival rate at lower concentration (0.1 and 0.5 µM/L), at 48 hr incubation. However, there was no statistically significant difference between the CUR and N-CUR groups on cell survival rate at both 48 and 72 hr incubation. When compared between the concentrations of the same group, significantly higher cell viability ( P = .001) was observed at lower concentrations (0.1, 0.5 µM/L) in both test groups after incubation for 48 and 72 hr. Conclusion: Both CUR and N-CUR have a dose-dependent effect on human derived MSCs survival when incubated for 48 hr, whereas N-CUR shows increased cell survival rate even at 72 hr of incubation. Although, the cautious use of CUR and N-CUR at higher concentrations is recommended.

Evidence for Killing of Mesenchymal Stem Cells (MSC) by Autologous Natural Killer Lymphocytes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1290-1290 ◽  
Author(s):  
Alessandro Poggi ◽  
Anna-Maria Massaro ◽  
Simone Negrini ◽  
Ivana Pierri ◽  
Manuela Balocco ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Natural Killer ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Lineage ◽  
Culture Conditions ◽  
Inhibitory Receptors

Abstract In this study, Mesenchymal Stem Cells (MSC) were obtained from bone marrow of 10 patients suffering from acute myeloid leukemia (AML), six M0/1 two M2, and two M5 (according to the FAB classification), 8 out of 10 in post-chemotherapy complete remission. These cells differentiated into adipocytes or osteoblasts under appropriate culture conditions. MSC were CD44+, CD73a+ CD73b+ CD105+, beta1 integrin+, ICAM1+, HLA-I+, HLA-II+ (variable proportions), CD45−, CD31−, CD34− and they constitutively expressed the stress-inducible MHC-related molecules MIC-A and the UL16 (induced at the surface of cells infected by cytomegalovirus) binding protein ULBP3. These molecules are reported ligands for the NKG2D receptor expressed by natural killer (NK) and CD8+ T lymphocytes, effector cells that are thought to play a role in host defence against tumors. NK cells have also been shown to regulate normal differentiation of hemopoietic precursor into the myeloid or lymphoid cell lineage. Moreover, it has been stated that NK cells are not able to damage autologous cells, as they receive negative signals through inhibitory receptors, including killer Ig-like receptors (KIR) or C-type lectin inhibitory receptors (CLIR), which bind to HLA-I discrete alleles. Surprisingly, we found that autologous IL2-activated, but not freshly isolated, NK cells lysed MSC, while T lymphocytes did not kill self or non-self MSC. Binding of ICAM-1 expressed by MSC to its receptor, the integrin LFA-1, expressed by NK cells plays a key role in MSC/NK interaction. More importantly, NKG2D/MICA and/or NKG2D/ULBP3 engagement is responsible for the delivery of lethal hit. Conversely, it appears that HLA-I molecules do not protect MSC from NK cell-mediated injury. Taken together, these data suggest that NK cells, when activated as it may occur during the first response to viral infections, are able to eliminate MSC, thus altering the normal interactions with hemopoietic precursors and possibly affecting their differentiation. This mechanism might also contribute to the development of aberrant precursors as observed in acute leukaemias.

scholarly journals Cholesterol Retards Senescence in Bone Marrow Mesenchymal Stem Cells by Modulating Autophagy and ROS/p53/p21Cip1/Waf1Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Mingyu Zhang ◽  
Yue Du ◽  
Renzhong Lu ◽  
You Shu ◽  
Wei Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Cellular Senescence ◽  
Dependent Manner ◽  
Cycle Arrest ◽  
Marrow Mesenchymal Stem Cells ◽  
Dose Dependent ◽  
Increased Activity

In the present study, we demonstrated that bone marrow mesenchymal stem cells (BMSCs) of the 3rd passage displayed the senescence-associated phenotypes characterized with increased activity of SA-β-gal, altered autophagy, and increased G1 cell cycle arrest, ROS production, and expression of p53 andp21Cip1/Waf1compared with BMSCs of the 1st passage. Cholesterol (CH) reduced the number of SA-β-gal positive cells in a dose-dependent manner in aging BMSCs induced by H2O2and the 3rd passage BMSCs. Moreover, CH inhibited the production of ROS and expression of p53 andp21Cip1/Waf1in both cellular senescence models and decreased the percentage of BMSCs in G1 cell cycle in the 3rd passage BMSCs. CH prevented the increase in SA-β-gal positive cells induced by RITA (reactivation of p53 and induction of tumor cell apoptosis, a p53 activator) or 3-MA (3-methyladenine, an autophagy inhibitor). Our results indicate that CH not only is a structural component of cell membrane but also functionally contributes to regulating cellular senescence by modulating cell cycle, autophagy, and the ROS/p53/p21Cip1/Waf1signaling pathway.

Sodium Butyrate Pre-Treatment Enhance Differentiation of Bone Marrow Mesenchymal Stem Cells (BM-MSCs) into Hepatocytes and Improve Liver Injury

2021 ◽  
Vol 21 ◽  
Author(s):  
Qiu-Yun Li ◽  
Juan Chen ◽  
Yong-Heng Luo ◽  
Wei Zhang ◽  
En-Hua Xiao
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Dependent Manner ◽  
Hepatic Differentiation ◽  
Marrow Mesenchymal Stem Cells ◽  
Specific Factors ◽  
Pre Treatment ◽  
Dose Dependent

Objective: The treatment of liver failure by stem cell transplantation has attracted growing interest. Herein, we aim to explore the role of sodium butyrate (NaB) in the hepatic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) under liver-specific factors induction in vitro and vivo. Materials & Methods: We isolated BM-MSCs from the mononuclear cell fraction of rabbit bone marrow samples, and identified the cells by Immunophenotypic analysis. We investigated the effects of different concentrations and induction conditions. The histone deacetylase inhibitor NaB induced hepatic differentiation of BM-MSCs under liver-specific factors induction in vitro. Morphological features, liver-specific gene and protein expression, and functional analyses in vitro and vivo were performed to evaluate the hepatic differentiation of BM-MSCs. Results: Our results showed that pre-treated NaB inhibited the expression of liver-specific protein in a dose-dependent manner. The induction efficiency of NaB with 24h pre-treatment was higher than that of NaB continuous intervention. 0.5 mM 24h NaB pre-treated cells can improve liver tissue damage in vivo. And the liver ALB, AAT and the serum TP were significantly increased, while the serum ALT was significantly reduced. Conclusion: Continuous NaB treatment can inhibit BM-MSCs proliferation in a dose-dependent manner at a certain concentration range. 0.5 mM 24h pre-treatment of NaB enhanced differentiation of BM-MSCs into hepatocytes and improves liver injury in vitro and vivo.

Bone Marrow–Derived Mesenchymal Stem Cells Promote Angiogenic Processes in a Time- and Dose-Dependent Manner In Vitro

2009 ◽  
Vol 15 (9) ◽  
pp. 2459-2470 ◽  
Author(s):  
Garry P. Duffy ◽  
Tabassum Ahsan ◽  
Timothy O'Brien ◽  
Frank Barry ◽  
Robert M. Nerem
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Dependent Manner ◽  
Dose Dependent

scholarly journals Differential natural killer cell–mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes

2007 ◽  
Vol 204 (12) ◽  
pp. 3027-3036 ◽  
Author(s):  
Galit Alter ◽  
Maureen P. Martin ◽  
Nickolas Teigen ◽  
William H. Carr ◽  
Todd J. Suscovich ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Activity ◽  
Cell Contact ◽  
Target Cells ◽  
Dependent Manner ◽  
Hiv 1

Decline of peak viremia during acute HIV-1 infection occurs before the development of vigorous adaptive immunity, and the level of decline correlates inversely with the rate of AIDS progression, implicating a potential role for the innate immune response in determining disease outcome. The combined expression of an activating natural killer (NK) cell receptor, the killer immunoglobulin-like receptor (KIR) 3DS1, and its presumed ligand, human leukocyte antigen (HLA)–B Bw4-80I, has been associated in epidemiological studies with a slow progression to AIDS. We examined the functional ability of NK cells to differentially control HIV-1 replication in vitro based on their KIR and HLA types. NK cells expressing KIR3DS1 showed strong, significant dose- and cell contact–dependent inhibition of HIV-1 replication in target cells expressing HLA-B Bw4-80I compared with NK cells that did not express KIR3DS1. Furthermore, KIR3DS1+ NK cells and NKLs were preferentially activated, and lysed HIV-1 infected target cells in an HLA-B Bw4-80I–dependent manner. These data provide the first functional evidence that variation at the KIR locus influences the effectiveness of NK cell activity in the containment of viral replication.

scholarly journals Restoring Innate and Adaptive Immune Repertoire in Multiple Myeloma for Therapeutic Application

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4398-4398
Author(s):  
Rafael Alonso Fernández ◽  
Laetitia Pierre-Louis ◽  
Rao Prabhala ◽  
Yan Xu ◽  
Joaquin Martinez-Lopez ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Adaptive Immunity ◽  
Fold Increase ◽  
Effector Memory ◽  
Dependent Manner ◽  
Innate And Adaptive Immunity ◽  
Equity Ownership ◽  
Dose Dependent

Despite advances and improvements in survival, majority of multiple myeloma (MM) patients ultimately relapses. Extensive analysis on the properties of tumor cells has provided interesting insights into the disease biology allowing for the identification of novel targets and development of related therapeutics. However, the key microenvironmental influences, especially immune microenvironment, that drive the disease and impact outcome remain to be fully characterized. We have now performed both single cell RNA-sequencing and high-dimensional CyTOF analysis of both peripheral blood (PBMC) and bone marrow mononuclear cells (BMMC) from MM patients and healthy donors (HD) and evaluated both phenotypic and functional state of the MM immune repertoire. In addition to humoral immunodeficiency impacting aberrations in B-cell subsets (B1a, B1b, B2 and Breg cells) and the disfunction in the adaptive immune system including an increase in the immunosuppressive cells (Tregs or myeloid-derived suppressor cells), a significant impairment of the innate immunity was identified in MM patients with a progressive decline in functional state of natural killer (NK) cells. Additionally, a lower expression of the activating receptors NKG2D and NKp46 as opposed to a higher expression of certain inhibitory KIR receptors was observed in NK cells from MM patients compared to HD. This immunosuppressive microenvironment allows tumor immune escape and ultimately myeloma cell growth. To overcome some of the immune dysfunction observed in MM, we have evaluated the role of IL15, a key player in both innate and adaptive immunity, with antitumor activity via enhancing both NK and memory T cell functions. Using extensive flow cytometry-based analysis, we evaluated impact of recombinant IL15 on PBMC from HD and MM patients at different stages of disease. Treatment with recombinant IL15 rescued the immune effector cell decline observed in MM patients. Specifically, a 2.9-fold-increase in CD8+ CD45RO+ CCR7- effector memory T cells and a 1.5-fold-increase in NK populations in both HD and MM PBMC was observed. For a subset of MM patients, we have also confirmed these positive effects on BMMC. Importantly, cytotoxicity tests revealed an improvement in NK cell effector functions leading to increased tumor cell recognition and killing, while we did not observe any direct effect of IL15 on growth and viability of MM cells. Integration of IL15 in the immunotherapeutic arsenal is limited by the unfavorable pharmacokinetic properties. Therefore, for clinical application and to restore both innate and adaptive immunity, we evaluated impact of NKTR-255, a polymer-conjugated IL15 receptor agonist designed to engage the IL-15 pathway to stimulate and expand natural killer (NK) cells and promote the survival and expansion of central memory CD8+ T cells without inducing suppressive regulatory T cells. Treatment with NKTR-255 enhanced the number and function of both NK and CD8+ effector memory T cell populations in PBMC from HD and MM patients in a dose dependent manner. Interestingly, the natural killer T (NKT) cells, heterogeneous group of T cells that share properties of both T cells and NK cells with important role in MM, were also increased in number by NKTR-255. To evaluate if NKTR-255 increases NK recognition of MM cells, cytotoxicity tests were performed using several MM cell lines and primary MM cells as targets, and both NK cells purified from PBMC of HD and MM patients as effectors. NKTR-255 was able to revert the inhibitory status of NK cells from MM patients (via induction of NKG2D expression), and significantly increase NK susceptibility of the MM cells in a dose dependent manner. Taken together, our data suggest a significant impact of NKTR-255 on the activation of effector cell function to efficiently target MM cells. This study has important translational implications and highlights the importance of restoring the balance between innate and adaptive immunity in MM. Disclosures Miyazaki: Nektar Therapeutics: Employment, Equity Ownership. Madakamutil:Nektar Therapeutics: Employment, Equity Ownership. Munshi:Amgen: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Oncopep: Consultancy.

scholarly journals Contact-dependent Stimulation and Inhibition of Dendritic Cells by Natural Killer Cells

2002 ◽  
Vol 195 (3) ◽  
pp. 335-341 ◽  
Author(s):  
Diego Piccioli ◽  
Silverio Sbrana ◽  
Emiliano Melandri ◽  
Nicholas M. Valiante
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Types ◽  
Cell Contact ◽  
Dependent Manner ◽  
Tnf Α ◽  
Dominant Feature ◽  
Dc Maturation

Natural killer (NK) cells and dendritic cells (DCs) are two distinct cell types of innate immunity. It is known that the in vitro interaction of human NK cells with autologous DCs results in DC lysis. Here we show that contact-dependent interactions between activated human NK cells and immature DCs (iDCs) provides a “control switch” for the immune system. At low NK/DC ratios, this interaction dramatically amplifies DC responses, whereas at high ratios it completely turns off their responses. Specifically, culture of activated human NK cells with iDCs, at low NK/DC ratios (1:5), led to exponential increases in DC cytokine production, which were completely dependent on cell-to-cell contact. DC maturation was also driven by cognate interactions with NK cells and maturation was dependent on endogenously produced TNF-α in the culture. At slightly higher NK/DC ratios (5:1), inhibition of DC functions was the dominant feature due to potent killing by the autologous NK cells. Resting NK cells also stimulated autologous DC maturation in a TNF-α/contact-dependent manner, however, increasing the NK/DC ratio only led to an enhancement of this effect.

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