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

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.

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

Cells ◽

10.3390/cells8010022 ◽

2019 ◽

Vol 8 (1) ◽

pp. 22 ◽

Cited By ~ 19

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.

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High Throughput Transcriptome Profiling of Lithium Stimulated Human Mesenchymal Stem Cells Reveals Priming towards Osteoblastic Lineage

PLoS ONE ◽

10.1371/journal.pone.0055769 ◽

2013 ◽

Vol 8 (1) ◽

pp. e55769 ◽

Cited By ~ 36

Author(s):

Neeraj Kumar Satija ◽

Deepa Sharma ◽

Farhat Afrin ◽

Rajendra P. Tripathi ◽

Gurudutta Gangenahalli

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

High Throughput ◽

Human Mesenchymal Stem Cells ◽

Transcriptome Profiling ◽

Osteoblastic Lineage

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Human Mesenchymal Stem Cells Induce T Cell Anergy and Downregulate T Cell Allo-Responses via the TH2 Pathway: Relevance to Tissue Engineering Human Heart Valves

Tissue Engineering ◽

10.1089/ten.2006.12.ft-168 ◽

2006 ◽

Vol 0 (0) ◽

pp. 060913044658034

Author(s):

Puspa Batten ◽

Padmini Sarathchandra ◽

Joseph W. Antoniw ◽

Szun Szun Tay ◽

Mark W. Lowdell ◽

...

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Human Heart ◽

Heart Valves ◽

Human Mesenchymal Stem Cells ◽

T Cell Anergy ◽

Cell Anergy

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

Transplantation Proceedings ◽

10.1016/j.transproceed.2013.12.059 ◽

2014 ◽

Vol 46 (5) ◽

pp. 1638-1641 ◽

Cited By ~ 11

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

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Human Mesenchymal Stem Cells Induce T Cell Anergy and Downregulate T Cell Allo-Responses via the TH2 Pathway: Relevance to Tissue Engineering Human Heart Valves

Tissue Engineering ◽

10.1089/ten.2006.12.2263 ◽

2006 ◽

Vol 12 (8) ◽

pp. 2263-2273 ◽

Cited By ~ 128

Author(s):

Puspa Batten ◽

Padmini Sarathchandra ◽

Joseph W. Antoniw ◽

Szun Szun Tay ◽

Mark W. Lowdell ◽

...

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Human Heart ◽

Heart Valves ◽

Human Mesenchymal Stem Cells ◽

T Cell Anergy ◽

Cell Anergy

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Interleukin-17A: A T-Cell-Derived Growth Factor for Murine and Human Mesenchymal Stem Cells

Stem Cells ◽

10.1634/stemcells.2005-0156 ◽

2006 ◽

Vol 24 (6) ◽

pp. 1512-1518 ◽

Cited By ~ 40

Author(s):

Weitao Huang ◽

Vincent La Russa ◽

Azam Alzoubi ◽

Paul Schwarzenberger

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Growth Factor ◽

Human Mesenchymal Stem Cells ◽

Interleukin 17A

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T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression

Journal of Biomedical Science ◽

10.1007/s11373-004-8183-7 ◽

2005 ◽

Vol 12 (1) ◽

pp. 47-57 ◽

Cited By ~ 384

Author(s):

Elena Klyushnenkova ◽

Joseph D Mosca ◽

Valentina Zernetkina ◽

Manas K Majumdar ◽

Kirstin J Beggs ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Human Mesenchymal Stem Cells ◽

T Cell Responses ◽

Cell Responses

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Mesenchymal Stem Cells Inhibit Th17 Differentiation through PGE2 Production.

Blood ◽

10.1182/blood.v114.22.3633.3633 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3633-3633

Author(s):

Raine Tatara ◽

Katsutoshi Ozaki ◽

Lekuni Oh ◽

Keiko Hatanaka ◽

Akiko Meguro ◽

...

Keyword(s):

Nitric Oxide ◽

Stem Cells ◽

Cell Proliferation ◽

T Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

T Cell Proliferation ◽

Th17 Differentiation ◽

Treg Differentiation ◽

Immunomodulatory Function

Abstract Abstract 3633 Poster Board III-569 Mesenchymal stem cells (MSCs) possess an immunomodulatory function and show promise as a cell therapy for graft-versus-host disease (GVHD). In a phase II study in Europe, injections of MSCs caused 60-70% overall response rate, with longer survival of complete responder. In contrast to its clinical efficacy, the molecular mechanism(s) underlying immunomodulation by MSCs has not been fully established. Prostaglandin E2 (PGE2), tumor growth factor-b1 (TGF-b1), and indoleamine-2,3-dioxygenase have been reported to mediate the immunomodulatory function of MSCs, and we reported evidence that nitric oxide is also a mediator (Blood 2007, 109, 228). Th17 is a recently recognized differentiation category, in which CD4 cells produce IL-17. It has been reported that Th17 is crucial for experimental autoimmune encephalomyelitis (a model of the human disease, multiple sclerosis) and is also thought to be important in other autoimmune diseases. Regulatory T cells (Treg) are another newly recognized differentiation category, in which CD4 T cells have high levels of Foxp3 expression and suppress T cell proliferation. It has been reported that Th17 and Treg can be induced by incubation with TGF-b1 and IL-6 or IL-21, and TGF-b1 and IL-2, respectively, and that these two differentiations are in a reciprocal relationship. Whereas the role of Th17 in GVHD is still controversial, Treg has been reported to suppress GVHD in a mouse model. To elucidate the molecular mechanism(s) of the immunomodulatory function of MSCs, we herein sought to identify the effects of MSCs on these relatively new differentiations. MSCs inhibit Th17 differentiation even in conditions in which growth is not completely inhibited. Interestingly, an inhibitor of prostaglandin production, indomethacin, and an inhibitor of indoleamine 2,3-dioxygenase, 1-methyltryptophan, partially restore Th17 differentiation, whereas inhibitors of nitric oxide synthase do not. These results suggest that PGE2 and depletion of tryptophan, but not nitric oxide, mediate inhibitory effects of MSCs on Th17. Additionally, we found that MSCs produced PGE2 when co-cultured with CD4 T cells in Th17 differentiation condition and PGE2 per se suppresses Th17 differentiation. Thus, our results suggest that MSCs block Th17 differentiation through PGE2 prodction. In contrast to Th17 differentiation, Treg differentiation was not significantly inhibited by MSCs. However, MSCs still inhibited proliferation of T cells under these conditions, and T cell proliferation was restored by the addition of indomethacin. These results suggest that MSCs inhibit proliferation but not Treg differentiation through PGE2 production. The mechanism by which PGE2 differentially regulates these differentiations is unknown and remains an area for further investigation. Disclosures: Ozawa: Alexion: Research Funding.

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Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness

Blood ◽

10.1182/blood-2004-07-2921 ◽

2005 ◽

Vol 105 (5) ◽

pp. 2214-2219 ◽

Cited By ~ 703

Author(s):

Shaul Beyth ◽

Zipora Borovsky ◽

Dror Mevorach ◽

Meir Liebergall ◽

Zulma Gazit ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Human Mesenchymal Stem Cells ◽

Cell Responses ◽

Dependent Inhibition ◽

Dose Dependent Inhibition ◽

Antigen Presenting ◽

Dose Dependent

AbstractInfusion of either embryonic or mesenchymal stem cells prolongs the survival of organ transplants derived from stem cell donors and prevents graft-versus-host-disease (GVHD). An in-depth mechanistic understanding of this tolerization phenomenon could lead to novel cell-based therapies for transplantation. Here we demonstrate that while human mesenchymal stem cells (hMSCs) can promote superantigen-induced activation of purified T cells, addition of antigen-presenting cells (APCs; either monocytes or dendritic cells) to the cultures inhibits the T-cell responses. This contact- and dose-dependent inhibition is accompanied by secretion of large quantities of interleukin (IL)–10 and aberrant APC maturation, which can be partially overridden by the addition of factors that promote APC maturation (ie, lipopolysaccharide [LPS] or anti-CD40 monoclonal antibody [mAb]). Thus, our data support an immunoregulatory mechanism wherein hMSCs inhibit T cells indirectly by contact-dependent induction of regulatory APCs with T-cell–suppressive properties. Our data may reveal a physiologic phenomenon whereby the development of a distinct APC population is regulated by the tissue's cellular microenvironment.

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