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Natural killer cells, which play a pivotal role in the establishment and maintenance of normal pregnancy, are the most abundant leukocytes at the fetomaternal interface that their subsets frequencies and cytokine profile are influential factors in the preservation of the decidual tolerogenic microenvironment. Any imbalance in NK cells' frequency and functions could be associated with pregnancy failure.Mesenchymal stem cells (MSCs) are shown to have immunomodulatory effects on NK cells and their cytokine profile. The purpose of this study is to evaluate the impact of MSCs therapy on the cytokine profiles and subpopulations of NK cells in a murine model of recurrent pregnancy loss. Adipose-derived MSCs were injected intraperitoneally to the abortion-prone mice on Day 4.5 of gestation. The abortion rate was determined after MSCs administration and the frequency and cytokine profiles of the different subsets of NK cells were determined using the flow cytometry. Our results showed that, in abortion-prone mice, the frequency of CD49b + NK cells was significantly higher than normal pregnant mice that decreased after therapy. We also demonstrated that MSCs downregulated the production of IFN-γ and upregulated IL-4 and IL-10 production by uNK cells. These findings indicate that MSCs can decrease the infiltration of CD49b + NK cells to the fetomaternal interface and modulate the cytokine profile of NK cells from inflammatory to tolerogenic profile and thereby improve the tolerogenic microenvironment at the fetomaternal interface in benefit of pregnancy maintenance.

Sirtuins are Class III protein deacetylases with seven conserved isoforms. In general, Sirtuins are highly activated in starving cells in response to stringent conditions, in which levels of NAD+ are increased. Each member of the Sirtuin family is prominently involved in the regulation of myriad fundamental biological processes including inflammation, proliferation, cell survival, DNA repair and metabolism. Sirtuins can also interact with various signaling pathways and factors such as hypoxia-inducible factors (HIFs), mitogen-activated protein kinases (MAPKs), nuclear factor-κB (NF-κB) and the Notch pathway, yet these interactions are demonstrated to be rather complicated. Therefore, deficiency in each member of the Sirtuin family results in severe developmental defects and irregularities both in animals and humans. Currently, a rapidly expanding body of evidence supports that Sirtuins can improve the pregnancy outcome. In fact, each Sirtuin isoform plays distinct yet fundamental roles in controlling folliculogenesis, oocyte meiotic maturation, oocyte aging, trophoblast functions, feto-maternal inflammation and placental angiogenesis and oxidative stress. Consequently, alterations in Sirtuin levels can be a pivotal intermediary step in the pathogenesis of several pregnancy disorders such as fetal growth retardation, preeclampsia and the HELLP syndrome. Furthermore, Sirtuins also appear to be involved in the regulation of parturition and pregnancy complications caused by maternal obesity and diabetes. In this review, we shall first address Sirtuin regulation and functions including their interactions with the most important signaling pathways involved in pregnancy. Then, we will focus on the pivotal roles of Sirtuins in female reproductive functions, normal pregnancy, parturition and pregnancy complications.

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