Deficiency of monoclonal non‐specific suppressor factor beta (MNSFB) promotes pregnancy loss in mice

Abstract

Maternal immune tolerance to the semi-allogenic fetus is required for successful pregnancy in mammals. Monoclonal nonspecific suppressor factor beta (MNSFB) is an immunosuppressive factor present in uterine epithelial and stromal cells, as well as in macrophages and T cells. Although the functional neutralization of MNSFB using specific antibodies against it lead to failed embryo implantation in mice, the exact role of MNSFB at the fetal-maternal interface remains unclear. The present study generated conditional heterozygous Mnsfb-deficient (Mnsfb(+/) (-) ) mice using the LoxP/Cre system. Western-blot analyses showed that uterine MNSFB protein in Mnsfb(+/-) mice was remarkably down-regulated compared to that in the wild-type (Mnsfb(+/+) ) mice. The litter size of female Mnsfb(+/-) mice was significantly reduced, which corresponded to developmental failure of embryos beyond Day 11 of pregnancy. The expression level of MNSFB protein was also lower in the failing compared to the normal embryos. An aberrant interaction between the embryos of Day-4 pregnant wild-type mice and endometrial stromal cells of female Mnsfb(+/-) mice was observed in vitro. The uterine Day-5 abundance of P53, BAX, and BCL-G in pregnant Mnsfb(+/-) mice was significantly decreased compared to that of wild-type mice, whereas the expression of P27 and tumor necrosis factor alpha (TNFA) was elevated. By comparison, the levels of MNSFB and BAX proteins in human decidual tissues obtained from recurrent spontaneous miscarriage patients were significantly reduced compared to those obtained from legal medial abortion, highlighting the involvement of MNSFB in the pathogenesis of recurrent spontaneous miscarriage. Together, these results demonstrated that a deficiency in MNSFb is associated with pregnancy loss, probably through reduced P53 and/or increased TNFA production at the fetal-maternal interface.

Decreased NDRG1 expression is associated with pregnancy loss in mice and attenuates the in vitro decidualization of endometrial stromal cells

“…Mnsf-beta +/− mice (Gu, He et al, 2015). As expected, uterine NDRG1 expression was significantly decreased in the mifepristone-induced pregnancy loss mice (Figure 4a).…”

“…In our previous studies, two pregnancy loss models were established in mice as follows: one is the mifepristone (RU486)‐treated mouse model (Yang, Yu et al, ), and the other is the monoclonal nonspecific suppressor factor ( MNSF ) ‐beta deficiency mouse model (Gu, He et al, ). Pregnant mice were treated with RU486 (25 μg per mouse) on Day 8 of pregnancy (D8), and the uterine tissues were collected on Day 10 of pregnancy (D10, n = 3).…”

“…If NDRG1 is involved in the establishment and/or maintenance of pregnancy, the deficiency in NDRG1 protein might lead to pregnancy loss. Thus, to observe the correlation between the uterine NDRG1 expression level and pregnancy loss, we detected uterine NDRG1 expression in two different mouse models with the typical phenotypes of pregnancy loss previously established in our lab: mifepristone‐treated mice (Yang, Yu et al, ) and heterozygous Mnsf‐beta +/− mice (Gu, He et al, ). As expected, uterine NDRG1 expression was significantly decreased in the mifepristone‐induced pregnancy loss mice (Figure a).…”

“…The uteri were collected from two different pregnancy loss mouse models that were established in our lab. In our previous study, we generated heterozygous Mnsf‐beta +/− mice and found that a lower fertility level was associated with the Mnsf‐beta‐ deficient mice, whereas the number of implantation embryos was normal in the Mnsf‐beta +/− mice; hence, the Mnsf‐beta‐ deficient mice can be used as a spontaneous abortion mouse model (Gu, He et al, ). We collected the uteri from D5 wild‐type mice and from D5 Mnsf‐beta +/− mice ( n = 3) and stored them at −80°C.…”

MNSFβ Promotes the Proliferation and Migration of Human Extravillous Trophoblast Cells and the Villus Expression Level of MNSFβ Is Decreased in Recurrent Miscarriage Patients

“…Subsequently, roles of MNSFβ in cell apoptosis were also demonstrated [10, 11]. In our previous studies, a decreased MNSFβ expression was observed in decidual tissues of RM patients [12], and it was also found that immunoneutralization of MNSFβ inhibited the mouse embryo implantation [13] and the reduced uterine MNSFβ expression in heterozygous MNSFβ-deficient ( MNSFβ +/− ) female mice caused the early pregnancy loss, suggesting that MNSFβ plays a key role at the maternal-fetal interface during the pregnancy process in mice [12].…”