Inhibition of T-Cell Proliferation by Murine Multipotent Mesenchymal Stromal Cells is Mediated by CD39 Expression and Adenosine Generation

Sattler, Christine; Steinsdoerfer, Manuela; Offers, Monika; Fischer, E.; Schierl, Rudolf; Heseler, Kathrin; Däubener, Walter; Seißler, Jochen

doi:10.3727/096368910x546553

Cited by 75 publications

(78 citation statements)

References 61 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Adding a parenthesis to this subject, CD39 expression by MSCs has been subject to conflicting observations [177]. In contrast to our observations [175] and others [178,179], some authors describe a lack or low CD39 expression by MSCs [176,180]. In our view, this might be due to specific experiment design or to antibody variation.…”

Section: Mscs and Adenosinecontrasting

confidence: 55%

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

Bravo

Carvalho

Saldanha-Araújo

2016

Purinergic Signalling

View full text Add to dashboard Cite

Adenosine is an important molecule that exerts control on the immune system, by signaling through receptors lying on the surface of immune cells. This nucleotide is produced, in part, by the action of the ectoenzymes CD39 and CD73. Interestingly, these proteins are expressed on the cell surface of regulatory T-cells (Tregs) and mesenchymal stromal cells (MSCs)-two cell populations that have emerged as potential therapeutic tools in the field of cell therapy. In fact, the production of adenosine constitutes a mechanism used by both cell types to control the immune response. Recently, great scientific progress was obtained regarding the role of adenosine in the inflammatory environment. In this context, the present review focuses on the advances related to the impact of adenosine production over the immune modulatory activity of Tregs and MSCs, and how this nucleotide controls the biological functions of these cells. Finally, we mention the main challenges and hurdles to bring such molecule to clinical settings.

show abstract

Section: Mscs and Adenosinecontrasting

confidence: 55%

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

Bravo

Carvalho

Saldanha-Araújo

2016

Purinergic Signalling

View full text Add to dashboard Cite

show abstract

“…In line with this investigation, recent studies provided evidences that CD39 mediated the immune suppression of T cells by MSCs in a cell-to-cell contact manner [8,9]. Adenosine is an anti-inflammatory product of enzymatic hydrolysis of extracellular ATP by CD39 (ectoATPase) and CD73 (ecto-5′-AMP nucleotidase).…”

Section: Introductionmentioning

confidence: 58%

“…Recently, some studies have shown that murine MSCs could share the adjacent modulatory function of inflammatory immune responses with Treg cells through the mediation of the CD39/CD73 pathway [8,9]. CD39 is an extracellular enzyme that catalyzes ATP and ADP to AMP, followed by rapid dephosphorylation of AMP into adenosine by CD73.…”

Section: Discussionmentioning

confidence: 99%

CD39-mediated effect of human bone marrow-derived mesenchymal stem cells on the human Th17 cell function

Lee

Jeong

Kim

et al. 2013

Purinergic Signalling

View full text Add to dashboard Cite

This study investigated the immune-modulatory effects of human bone marrow-derived mesenchymal stem cells (hBMSCs) on human Th17 cell function through the CD39-mediated adenosine-producing pathway. The suppressive effects of hBMSCs were evaluated by assessing their effects on the proliferation of Th17 cells and the secretion of interferon (IFN)-γ and interleukin (IL)-17A by Th17 cells with or without anti-CD39 treatment. Changes in CD39 and CD73 expression on the T cells with or without co-culture of hBMSCs were evaluated by flow cytometry. hBMSCs effectively suppressed the proliferation of Th17 cells and the secretion of both IL-17A and IFN-γ from Th17 cells using by both flow cytometry and ELISA, while anti-CD39 treatment significantly reduced the inhibitory effects of hBMSCs on the proliferation and secretion of the Th17 cells. The hBMSCs induced increased expression of the CD39 and CD73 on T cells correlated with the suppressive function of hBMSCs, which was accompanied by increased adenosine production. Our data suggests that hBMSCs can effectively suppress immune responses of the Th17 cells via the CD39-CD73-mediated adenosine-producing pathway.

show abstract

“…Adenosine is readily formed from ATP by the sequential activity of CD39 and CD73 ectoenzymes, which are expressed on the MSC plasma membrane [27,28,[72][73][74]. When we tested ectonucleotidase expression, we found that more than 90% of BM-hMSCs were CD73 positive, whereas CD39 was expressed in a median of 25.6% of the cells (range: 14.8%-59.9%) (Supplementary Table S4).…”

Section: Bm-hmsc Differentiation Is Regulated By Different Signaling mentioning

confidence: 99%

Extracellular Purines Promote the Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells to the Osteogenic and Adipogenic Lineages

Ciciarello

Zini

Rossi

et al. 2013

Stem Cells and Development

102

101

View full text Add to dashboard Cite

Extracellular nucleotides are potent signaling molecules mediating cell-specific biological functions, mostly within the processes of tissue damage and repair and flogosis. We previously demonstrated that adenosine 5¢-triphosphate (ATP) inhibits the proliferation of human bone marrow-derived mesenchymal stem cells (BMhMSCs), while stimulating, in vitro and in vivo, their migration. Here, we investigated the effects of ATP on BM-hMSC differentiation capacity. Molecular analysis showed that ATP treatment modulated the expression of several genes governing adipogenic and osteoblastic (ie, WNT-pathway-related genes) differentiation of MSCs. Functional studies demonstrated that ATP, under specific culture conditions, stimulated adipogenesis by significantly increasing the lipid accumulation and the expression levels of the adipogenic master gene PPARc (peroxisome proliferator-activated receptor-gamma). In addition, ATP stimulated osteogenic differentiation by promoting mineralization and expression of the osteoblast-related gene RUNX2 (runt-related transcription factor 2). Furthermore, we demonstrated that ATP stimulated adipogenesis via its triphosphate form, while osteogenic differentiation was induced by the nucleoside adenosine, resulting from ATP degradation induced by CD39 and CD73 ectonucleotidases expressed on the MSC membrane. The pharmacological profile of P2 purinergic receptors (P2Rs) suggests that adipogenic differentiation is mainly mediated by the engagement of P2Y1 and P2Y4 receptors, while stimulation of the P1R adenosine-specific subtype A2B is involved in adenosine-induced osteogenic differentiation. Thus, we provide new insights into molecular regulation of MSC differentiation.

show abstract

Inhibition of T-Cell Proliferation by Murine Multipotent Mesenchymal Stromal Cells is Mediated by CD39 Expression and Adenosine Generation

Cited by 75 publications

References 61 publications

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

CD39-mediated effect of human bone marrow-derived mesenchymal stem cells on the human Th17 cell function

Extracellular Purines Promote the Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells to the Osteogenic and Adipogenic Lineages

Contact Info

Product

Resources

About