Introduction: Innate immune reactions against islet grafts are considered a major obstacle for intraportal islet transplantation. We have previously reported that liver natural killer (NK) cells play a crucial role in the destruction of islets transplanted into the liver due to significant increase in the expression of TNF-related apoptosis-inducing ligand (TRAIL) and cytotoxicity against islets following islet transplantation into the liver. We focused on mesenchymal stem cells (MSCs), which have been shown to inhibit immune reactions, to prevent NK cell activation. In this study, we investigated the potential effects of MSCs on activated NK cells in the liver after islet transplantation.

Methods: To evaluate the phenotypical and functional alteration of liver NK cells, liver mononuclear cells (LMNCs) and bone marrow-derived MSCs were prepared from C57BL/6 mice. In the in vitro assays, LMNCs were co-cultured with or without various concentrations of MSCs in the presence of IL-2 for 3 days, and the surface molecules on liver NK cells were analyzed by flow cytometry. In the in vivo assays, MSCs were intraportally administered into the liver of C57BL/6 mice, and LMNCs were collected 3 or 5 days after MSCs administration for analyzing the phenotypical alterations of liver NK cells.

Results: Prostaglandin E2 (PGE2) was detected in the MSC culture medium. To evaluate the suppressive effect of PGE2, TRAIL expression in IL-2-stimulated liver NK cells was analyzed in the presence or absence of PGE2 (control), and the cells co-cultured with PGE2 showed significant suppression of TRAIL+ NK cells than that in the control (19.7% vs. 24.5%). Furthermore, TRAIL expression was significantly lower in IL-2-stimulated liver NK cells co-cultured with MSCs than in cells cultured without MSCs (5.7 ± 0.5% vs. 14.0 ± 3.1%, n=3). The proportion of TRAIL+ liver NK cells 3 days after intraportal administration of MSCs was significantly lower than that in the naive condition (14.3% vs. 38.3%).

Conclusion: We demonstrate for the first time that MSCs decrease the proportion of TRAIL+ liver NK cells both in vivo and in vitro. Our findings imply that MSCs co-transplantation could improve graft survival in islet transplantation by suppressing activated NK cells in the liver via the TRAIL-TRAIL receptor pathway.

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