scholarly journals Human Liver Stem Cells Suppress T-Cell Proliferation, NK Activity, and Dendritic Cell Differentiation

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Stefania Bruno ◽  
Cristina Grange ◽  
Marta Tapparo ◽  
Chiara Pasquino ◽  
Renato Romagnoli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
T Cell ◽  
Human Liver ◽  
T Cell Proliferation ◽  
Cell Contact ◽  
Adult Liver ◽  
Dendritic Cell Differentiation ◽  
Liver Stem Cells ◽  
Immunomodulatory Properties

Human liver stem cells (HLSCs) are a mesenchymal stromal cell-like population resident in the adult liver. Preclinical studies indicate that HLSCs could be a good candidate for cell therapy. The aim of the present study was to evaluate the immunogenicity and the immunomodulatory properties of HLSCs on T-lymphocytes, natural killer cells (NKs), and dendritic cells (DCs) in allogeneic experimental settings. We found that HLSCs inhibited T-cell proliferation by a mechanism independent of cell contact and dependent on the release of prostaglandin E2 (PGE2) and on indoleamine 2,3-dioxygenase activity. When compared with mesenchymal stromal cells (MSCs), HLSCs were more efficient in inhibiting T-cell proliferation. At variance with MSCs, HLSCs did not elicit NK degranulation. Moreover, HLSCs inhibited NK degranulation against K562, a NK-sensitive target, by a mechanism dependent on HLA-G release. When tested on DC generation from monocytes, HLSCs were found to impair DC differentiation and DCs ability to induce T-cell proliferation through PGE2. This study shows that HLSCs have immunomodulatory properties similar to MSCs, but, at variance with MSCs, they do not elicit a NK response.

Induction of Indoleamine 2,3-Dioxygenase Expression by Interferon-g in Human Mesenchymal Stem Cells Inhibits Graft Versus Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4698-4698
Author(s):  
Myoung Woo Lee ◽  
Dae Seong Kim ◽  
Hye Jin Kim ◽  
Meong Hi Son ◽  
Soo Hyun Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
T Cell Proliferation ◽  
Activated T Cells ◽  
Graft Versus Host ◽  
Ifn Γ ◽  
Immunomodulatory Properties

Abstract Abstract 4698 Background: It is important to overcome the limitations such as graft rejection and graft versus host disease (GvHD) in allogeneic hematopoietic stem cell transplantation. Mesenchymal stem cells (MSCs), which evoke only minimal immune reactivity, may have anti-inflammatory and immunomodulatory effects. Purpose: In this study, we aimed to identify the immunomodulatory properties of human MSCs and to elucidate the possible mechanism of their properties for clinical treatment of allogeneic conflicts using MSCs. Materials & Methods: We conducted a comparative analysis about the immunomodulatory properties of MSCs derived from adult human tissues, including bone marrow (BM), adipose tissues (AT), umbilical cord blood (CB), and cord Wharton's jelly (WJ), in vitro and in vivo models. Results: AT-MSCs, CB-MSCs, and WJ-MSCs effectively suppressed phytohemagglutinin (PHA)-induced T-cell proliferation as effectively as did BM-MSCs. Levels of interferon (IFN)-g secreted from activated T-cells increased over time, but these levels were significantly reduced when cocultured with each type of MSCs. In addition, expression of indoleamine 2,3-dioxygenase (IDO) increased in MSCs treated with IFN-γ via JAK/STAT1 signaling pathways. Treatment with anti-IFN-g antibodies, JAK1/2 inhibitor or STAT1 siRNA restored PHA-induced T-cell proliferation. Use of an antagonist, 1-methyl-L-tryptophan, also restored PHA-induced T-cell proliferation, suggesting that IDO contributes to IFN-g-induced immunosuppression in MSCs. Moreover, infusion of IFN-g-treated MSCs decreased symptoms for human peripheral blood-derived mononuclear cells-induced GvHD in NOD/SCID mice, which resulted in an increase of survival rate of in vivo GvHD model. Conclusion: These data indicate that IFN-γ produced by activated T-cells is correlated with induction of IDO expression in MSCs by IFN-γ receptor/JAK/STAT1 pathway, which resulted in suppression of T-cell proliferation. Our findings suggest that MSCs derived from BM, AT, CB, or WJ could be used for clinical treatment of allogeneic conflicts. Disclosures: No relevant conflicts of interest to declare.

Suppression of T-Cell Proliferation by and B7-H1 Expression on Human Liver-Derived Stem Cells

2015 ◽  
Vol 47 (3) ◽  
pp. 784-786
Author(s):  
I.K. Jang ◽  
J.H. Lee ◽  
H.H. Yoon ◽  
H.J. Park ◽  
Y.A. Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
T Cell ◽  
Human Liver ◽  
T Cell Proliferation

scholarly journals Assessment of the Immunosuppressive Potential of INF-γ Licensed Adipose Mesenchymal Stem Cells, Their Secretome and Extracellular Vesicles

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 22 ◽  
Author(s):  
Teresa Raquel Tavares Serejo ◽  
Amandda Évelin Silva-Carvalho ◽  
Luma Dayane de Carvalho Filiú Braga ◽  
Francisco de Assis Rocha Neves ◽  
Rinaldo Wellerson Pereira ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Extracellular Vesicles ◽  
Cellular Therapy ◽  
T Cell Proliferation ◽  
Cell Contact ◽  
A Cell ◽  
Immunomodulatory Function

There is an active search for the ideal strategy to potentialize the effects of Mesenchymal Stem-Cells (MSCs) over the immune system. Also, part of the scientific community is seeking to elucidate the therapeutic potential of MSCs secretome and its extracellular vesicles (EVs), in order to avoid the complexity of a cellular therapy. Here, we investigate the effects of human adipose MSCs (AMSCs) licensing with INF-γ and TLR3 agonist over AMSCs proliferation, migration, as well as the immunomodulatory function. Furthermore, we evaluated how the licensing of AMSCs affected the immunomodulatory function of AMSC derived-secretome, including their EVs. INF-γ licensed-AMSCs presented an elevated expression of indoleamine 2,3-dioxygenase (IDO), accompanied by increased ICAM-1, as well as a higher immunosuppressive potential, compared to unlicensed AMSCs. Interestingly, the conditioned medium obtained from INF-γ licensed-AMSCs also revealed a slightly superior immunosuppressive potential, compared to other licensing strategies. Therefore, unlicensed and INF-γ licensed-AMSCs groups were used to isolate EVs. Interestingly, EVs isolated from both groups displayed similar capacity to inhibit T-cell proliferation. EVs isolated from both groups shared similar TGF-β and Galectin-1 mRNA content but only EVs derived from INF-γ licensed-AMSCs expressed IDO mRNA. In summary, we demonstrated that INF-γ licensing of AMSCs provides an immunosuppressive advantage both from a cell-cell contact-dependent perspective, as well as in a cell-free context. Interestingly, EVs derived from unlicensed and INF-γ licensed-AMSCs have similar ability to control activated T-cell proliferation. These results contribute towards the development of new strategies to control the immune response based on AMSCs or their derived products.

Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 228-234 ◽  
Author(s):  
Kazuya Sato ◽  
Katsutoshi Ozaki ◽  
Iekuni Oh ◽  
Akiko Meguro ◽  
Keiko Hatanaka ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Stem Cells ◽  
Cell Proliferation ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Specific Inhibitor ◽  
T Cell Proliferation

Abstract The molecular mechanisms by which mesenchymal stem cells (MSCs) suppress T-cell proliferation are poorly understood, and whether a soluble factor plays a major role remains controversial. Here we demonstrate that the T-cell–receptor complex is not a target for the suppression, suggesting that downstream signals mediate the suppression. We found that Stat5 phosphorylation in T cells is suppressed in the presence of MSCs and that nitric oxide (NO) is involved in the suppression of Stat5 phosphorylation and T-cell proliferation. The induction of inducible NO synthase (NOS) was readily detected in MSCs but not T cells, and a specific inhibitor of NOS reversed the suppression of Stat5 phosphorylation and T-cell proliferation. This production of NO in the presence of MSCs was mediated by CD4 or CD8 T cells but not by CD19 B cells. Furthermore, inhibitors of prostaglandin synthase or NOS restored the proliferation of T cells, whereas an inhibitor of indoleamine 2,3-dioxygenase and a transforming growth factor–β–neutralizing antibody had no effect. Finally, MSCs from inducible NOS−/− mice had a reduced ability to suppress T-cell proliferation. Taken together, these results suggest that NO produced by MSCs is one of the major mediators of T-cell suppression by MSCs.

scholarly journals Intrinsic Variability Present in Wharton’s Jelly Mesenchymal Stem Cells and T Cell Responses May Impact Cell Therapy

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Fernanda Vieira Paladino ◽  
Luiz Roberto Sardinha ◽  
Carla Azevedo Piccinato ◽  
Anna Carla Goldberg
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Replicative Senescence ◽  
T Cell Response ◽  
Wharton’S Jelly ◽  
T Cell Proliferation ◽  
Intrinsic Variability ◽  
Wharton's Jelly

Wharton’s jelly mesenchymal stem cells (WJ-MSC) exhibit immunomodulatory effects on T cell response. WJ-MSC are easy to collect, process, and proliferate rapidly in culture, but information on the variability of individual cell samples impacting upon in vitro expansion, immunomodulatory potential, and aging processes is still lacking. We propose to evaluate the immunomodulatory cytokine profile and capacity to inhibit T cell proliferation of WJ-MSC progressing to replicative senescence in order to analyze if expected responses are affected. Our results show that the gene expression of immunomodulatory molecules varied among samples with no specific pattern present. In coculture, all WJ-MSC were capable of inhibiting mitogen-activated CD3+ T cell proliferation, although to different degrees, and each PBMC responded with a different level of inhibition. Thus, we suggest that each WJ-MSC displays unique behavior, differing in patterns of cytokine mRNA expression and immunomodulatory capacity. We believe that variability between samples may play a role in the effectiveness of WJ-MSC employed therapeutically.

scholarly journals Bone Morphogenetic Protein 6 Inhibits the Immunomodulatory Property of BMMSCs via Id1 in Sjögren’s Syndrome

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Yingying Su ◽  
Yi Gu ◽  
Ruiqing Wu ◽  
Hao Wang
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
T Cell Proliferation ◽  
Sjögren‘S Syndrome

Mesenchymal stem cells (MSCs) treatment has emerged as a promising approach for treating Sjögren’s syndrome (SS). Impaired immunoregulatory activities of bone marrow mesenchymal stem cells (BMMSCs) are found in both SS patients and animal models, and the underlying mechanism is poorly understood. Increased expression of BMP6 is reported to be related to SS. The aim herein was to determine the effects of BMP6 on BMMSCs function. BMMSCs were isolated from SS patients and NOD mice and showed a high level of BMP6 expression. The effects of BMP6 on BMMSCs function were investigated using in vitro BMMSCs differentiation and in vitro and in vivo T cell proliferation and polarization assays. BMP6 increased osteogenic differentiation of BMMSCs and inhibited the immunomodulatory properties of BMMSCs. BMP6 enhanced T cell proliferation and Th1/Th17 differentiation in a T cell-BMMSC coculture system. Mechanistically, BMP6 downregulated PGE2 and upregulated IFN-gamma via Id1 (inhibitor of DNA-binding protein 1). Neutralizing BMP6 and knockdown of Id1 could restore the BMMSCs immunosuppressive function both in vitro and in vivo. The present results suggest a novel role of Id1 in BMP-mediated MSCs function, which may contribute to a better understanding of the mechanism of action of MSCs in treating autoimmune diseases.

Chimeric Regulatory T cells Enhance HSC Engraftment in An Antigen-Specific Fashion.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2424-2424
Author(s):  
Yiming Huang ◽  
Larry D Bozulic ◽  
Thomas Miller ◽  
Hong Xu ◽  
Yujie Wen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Third Party ◽  
T Cell Proliferation ◽  
Hematopoietic Stem ◽  
Mixed Chimeras

Abstract Abstract 2424 Poster Board II-401 We previously reported that CD8+TCR- facilitating cells (FC) induce the generation of chimeric regulatory T cells (Treg) in vivo. Transplantation of a mixture of CD8+/TCR- FC and hematopoietic stem cells (HSC) into ablated recipients results in chimerism and tolerance. Treg harvested from the spleen of chimeras (chimeric Treg) potently increase long-term donor chimerism in secondary NOD recipient mice. Here, we evaluated whether chimeric Treg enhance engraftment of hematopoietic stem cells (HSC) in an antigen-specific manner. To prepare mixed chimeras (B6 → NOD), NOD recipients were conditioned with 950 cGy TBI and transplanted with 10,000 B6 HSC and 1,000 NOD HSC plus 45,000 CD8+TCR- B6 FC. At 5 weeks, CD8-CD4+CD25bright chimeric Treg were sorted from spleens of the mixed chimeras (B6 → NOD). 100,000 chimeric Treg were then mixed with 10,000 B6 HSC (donor-specific) + 10,000 B10.BR HSC (third-party) and transplanted into conditioned NOD recipients in competitive repopulation assays. NOD mice given HSC plus nonchimeric naïve B6 Treg or HSC alone served as controls. Two of the four animals that received HSC alone engrafted and exhibited an average of 6.7% donor B6 chimerism at 30 days, 11.2% at 60 days, and 10.6% at 90 days. Three of five animals given HSC plus naïve B6 Treg engrafted with 21.3% donor B6 chimerism at 30 days, 28.8% at 60 days, and 28.9% at 90 days. In contrast, eight of nine recipients of HSC + chimeric Treg engrafted. These animals exhibited a significantly higher level of donor B6 chimerism, ranging from 56.3% at 30 days, 75.4% at 60 days to 85% at 90 days (P = 0.034). None of the recipients engrafted with the MHC-disparate third-party B10.BR HSC. We then assessed the suppressive function of chimeric Tregin vitro by using MLR suppressor cell assays. CD8-/CD4+/CD25bright Treg were sorted from chimeric spleens 5 wks to 12 wks after HSC + FC transplantation. As shown in the Figure 1, Treg from naïve B6 mice resulted in 1.9 fold; 1.3 fold and 1.1 fold inhibition of proliferation at 1:1, 1:0.25, 1:0.125 responder/Treg ratios (n = 3). In contrast, chimeric Treg potently suppressed T cell proliferation by 10.5 fold; 3.2 fold; and 1.7 fold at responder/Treg ratios of 1:1, 1:0.25, 1:0.125 (n = 4). Chimeric Treg significantly suppressed T cell proliferation at responder/Treg ratios of 1:1 and 1:0.25 compared with naïve B6 Treg (P < 0.05). NOD responder splenocytes remained hypoproliferative in response to B6 stimulator and chimeric Treg compared with stimulator plus B6 Treg, suggesting that chimeric Treg are significantly more potent than naïve B6 Treg in suppressing effector T cell proliferation in vitro. These data show that chimeric Treg enhance donor B6 HSC engraftment but not third-party B10.BR HSC, demonstrating that chimeric Treg function in vivo in an antigen-specific fashion. These data also show that the mechanism of FC function in vivo is associated with the establishment of an antigen-specific regulatory feedback loop. Figure 1 Figure 1. Disclosures: Bozulic: Regenerex: Employment. Ildstad:Regenerex: Equity Ownership.

B7-H1 Inhibits T Cell Proliferation Through MHC Class II in Human Mesenchymal Stem Cells

2014 ◽  
Vol 46 (5) ◽  
pp. 1638-1641 ◽  
Author(s):  
I.K. Jang ◽  
H.H. Yoon ◽  
M.S. Yang ◽  
J.E. Lee ◽  
D.-H. Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Human Mesenchymal Stem Cells ◽  
Class Ii ◽  
T Cell Proliferation

Human Adipose Tissue-Derived Mesenchymal Stem Cells Induce Explosive T-Cell Proliferation

2010 ◽  
Vol 19 (12) ◽  
pp. 1843-1853 ◽  
Author(s):  
Meindert J. Crop ◽  
Carla C. Baan ◽  
Sander S. Korevaar ◽  
Jan N.M. Ijzermans ◽  
Willem Weimar ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
T Cell ◽  
Human Adipose Tissue ◽  
T Cell Proliferation

scholarly journals Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment

Blood ◽  
2013 ◽  
Vol 122 (5) ◽  
pp. 749-758 ◽  
Author(s):  
Francis Mussai ◽  
Carmela De Santo ◽  
Issa Abu-Dayyeh ◽  
Sarah Booth ◽  
Lynn Quek ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
T Cell Proliferation ◽  
Hematopoietic Stem ◽  
Key Points ◽  
Immunosuppressive Microenvironment ◽  
Acute Myeloid

Key Points AML blasts have an arginase-dependent ability to inhibit T-cell proliferation and hematopoietic stem cells. AML blasts have an arginase-dependent ability to modulate the polarization of monocytes.

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