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Role of gamma-secretase in human umbilical-cord derived mesenchymal stem cell mediated suppression of NK cell cytotoxicity.

Chatterjee D, Marquardt N, Tufa DM, Beauclair G, Low HZ, Hatlapatka T, Hass R, Kasper C, von Kaisenberg C, Schmidt RE, Jacobs R - Cell Commun. Signal (2014)

Bottom Line: The main soluble immunosuppressant was identified as prostaglandin (PG)-E2.IL-1 receptor activation and subsequent downstream signalling events were found to require gamma-secretase activity.Our findings shed light on this puzzling observation and identify new players in the NK cell-MSC crosstalk.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Mesenchymal stem cells (MSCs) are increasingly considered to be used as biological immunosuppressants in hematopoietic stem cell transplantation (HSCT). In the early reconstitution phase following HSCT, natural killer (NK) cells represent the major lymphocyte population in peripheral blood and display graft-vs-leukemia (GvL) effects. The functional interactions between NK cells and MSCs have the potential to influence the leukemia relapse rate after HSCT. Until date, MSC-NK cell interaction studies are largely focussed on bone marrow derived (BM)-MSCs. Umbilical cord derived (UC)-MSCs might be an alternative source of therapeutic MSCs. Thus, we studied the interaction of UC-MSCs with unstimulated allogeneic NK cells.

Results: UC-MSCs could potently suppress NK cell cytotoxicity in overnight cultures via soluble factors. The main soluble immunosuppressant was identified as prostaglandin (PG)-E2. Maximal PGE2 release involved IL-1β priming of MSCs after close contact between the NK cells and UC-MSCs. Interestingly, blocking gamma-secretase activation alleviated the immunosuppression by controlling PGE2 production. IL-1 receptor activation and subsequent downstream signalling events were found to require gamma-secretase activity.

Conclusion: Although the role of PGE2 in NK cell-MSC has been reported, the requirement of cell-cell contact for PGE2 induced immunosuppression remained unexplained. Our findings shed light on this puzzling observation and identify new players in the NK cell-MSC crosstalk.

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Phenotype of UC-MSCs. UC-MSCs were detached using accutase and stained with antibodies against CD14, CD19, CD34, CD45, CD73, CD90, CD105, and HLA-DR (shaded histograms) or isotype control antibodies (filled histograms).
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Fig1: Phenotype of UC-MSCs. UC-MSCs were detached using accutase and stained with antibodies against CD14, CD19, CD34, CD45, CD73, CD90, CD105, and HLA-DR (shaded histograms) or isotype control antibodies (filled histograms).

Mentions: The surface antigen expression patterns on the UC-MSCs were analysed using flow cytometry (Figure 1). CD73, CD90, and CD105 were highly expressed. MSCs lacked the expression of CD14, CD19, CD45, and HLA-DR on their cell surface. There was a very faint expression of CD34. The ability of the UC-MSCs to undergo chondrogenic, adipogenic and osteogenic differentiation was determined as described before (data not shown) [3]. Hence, the UC-MSCs fulfilled all the criteria recommended by the International Society for Cellular Therapy for identifying MSC [4].Figure 1


Role of gamma-secretase in human umbilical-cord derived mesenchymal stem cell mediated suppression of NK cell cytotoxicity.

Chatterjee D, Marquardt N, Tufa DM, Beauclair G, Low HZ, Hatlapatka T, Hass R, Kasper C, von Kaisenberg C, Schmidt RE, Jacobs R - Cell Commun. Signal (2014)

Phenotype of UC-MSCs. UC-MSCs were detached using accutase and stained with antibodies against CD14, CD19, CD34, CD45, CD73, CD90, CD105, and HLA-DR (shaded histograms) or isotype control antibodies (filled histograms).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4195898&req=5

Fig1: Phenotype of UC-MSCs. UC-MSCs were detached using accutase and stained with antibodies against CD14, CD19, CD34, CD45, CD73, CD90, CD105, and HLA-DR (shaded histograms) or isotype control antibodies (filled histograms).
Mentions: The surface antigen expression patterns on the UC-MSCs were analysed using flow cytometry (Figure 1). CD73, CD90, and CD105 were highly expressed. MSCs lacked the expression of CD14, CD19, CD45, and HLA-DR on their cell surface. There was a very faint expression of CD34. The ability of the UC-MSCs to undergo chondrogenic, adipogenic and osteogenic differentiation was determined as described before (data not shown) [3]. Hence, the UC-MSCs fulfilled all the criteria recommended by the International Society for Cellular Therapy for identifying MSC [4].Figure 1

Bottom Line: The main soluble immunosuppressant was identified as prostaglandin (PG)-E2.IL-1 receptor activation and subsequent downstream signalling events were found to require gamma-secretase activity.Our findings shed light on this puzzling observation and identify new players in the NK cell-MSC crosstalk.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Mesenchymal stem cells (MSCs) are increasingly considered to be used as biological immunosuppressants in hematopoietic stem cell transplantation (HSCT). In the early reconstitution phase following HSCT, natural killer (NK) cells represent the major lymphocyte population in peripheral blood and display graft-vs-leukemia (GvL) effects. The functional interactions between NK cells and MSCs have the potential to influence the leukemia relapse rate after HSCT. Until date, MSC-NK cell interaction studies are largely focussed on bone marrow derived (BM)-MSCs. Umbilical cord derived (UC)-MSCs might be an alternative source of therapeutic MSCs. Thus, we studied the interaction of UC-MSCs with unstimulated allogeneic NK cells.

Results: UC-MSCs could potently suppress NK cell cytotoxicity in overnight cultures via soluble factors. The main soluble immunosuppressant was identified as prostaglandin (PG)-E2. Maximal PGE2 release involved IL-1β priming of MSCs after close contact between the NK cells and UC-MSCs. Interestingly, blocking gamma-secretase activation alleviated the immunosuppression by controlling PGE2 production. IL-1 receptor activation and subsequent downstream signalling events were found to require gamma-secretase activity.

Conclusion: Although the role of PGE2 in NK cell-MSC has been reported, the requirement of cell-cell contact for PGE2 induced immunosuppression remained unexplained. Our findings shed light on this puzzling observation and identify new players in the NK cell-MSC crosstalk.

Show MeSH
Related in: MedlinePlus