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Although natural killer (NK) cells play a crucial role in the maintenance of a successful pregnancy, their cytotoxic activity should be tightly controlled. We hypothesized that endometrial mesenchymal stromal/stem cells (eMSCs) could potentially attenuate the functional features of NK cells. Herein, we assessed immunomodulatory effects of menstrual blood-derived stromal/stem cells (MenSCs), as a surrogate for eMSCs, on NK cells function. Our results showed that MenSCs induced proliferation of NK cells. However, IFN-γ/IL-1β pretreated MenSCs significantly inhibited NK cell proliferation. Of 41 growth factors tested, MenSCs produced lower levels of insulin-like growth factor binding proteins (IGFBPs) 1–4, VEGF-A, β-NGF, and M-CSF compared to bone marrow-derived mesenchymal stem cells (BMSCs). MenSCs displayed high activity of IDO upon IFN-γ treatment. The antiproliferative potential of IFN-γ/IL-1β-pretreated MenSCs was mediated through IL-6 and TGF-β. MenSCs impaired the cytotoxic activity of NK cells on K562 cells, consistent with the lower expression of perforin, granzymes A, and B. We also observed that  in vitro  decidualization of MenSCs in the presence of IFN-γ reduced the inhibitory effect of MenSCs on NK cell cytotoxicity against K562 target cells. Additionally, MenSCs were found to be prone to NK cell-mediated lysis in an MHC-independent manner. Our findings imply that dysregulation of NK cells in such pregnancy-related disorders as miscarriage may stem from dysfunctioning of eMSCs.

Human menstrual blood-derived stromal/stem cells modulate functional features of natural killer cells