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Prednisolone Alters Endometrial Decidual Cells and Affects Decidual-Trophoblast Interactions.

ABSTRACT: Poor pregnancy outcomes such as recurrent pregnancy loss (RPL) and preeclampsia are associated with impaired decidualization and abnormal trophoblast invasion. Emerging evidence suggests that use of corticosteroids, including prednisolone affects fertility by altering uterine function and may be associated with preeclampsia incidence. In this study, using primary and gestational-age appropriate tissue, we aimed to define the effect of prednisolone on human endometrial stromal fibroblast (hESF) decidualization and determine whether hESF decidualization in the presence of prednisolone would alter hESF regulation of trophoblast function. We found that prednisolone treatment reduced hESF cytokine expression (IL6, IL11, IL18, LIF, and LIFR) but had no effect on hESF expression or secretion of the classic markers of decidualization [prolactin (PRL) and IGFBP1]. Using proteomics we determined that prednisolone altered decidualized hESF protein production, enriching hESF proteins associated with acetylation and mitrochondria. Conditioned media from hESF decidualized in the presence of prednisolone significantly enhanced trophoblast outgrowth and trophoblast mRNA expression of cell motility gene PLCG1 and reduced trophoblast production of PGF. Prednisolone treatment during the menstrual cycle and 1st trimester of pregnancy might alter decidual interactions with other cells, including invasive trophoblast.

SUBMITTER: Grbac E

PROVIDER: S-EPMC8063028 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Trophoblast invasion likely depends on complex cross talk between the fetal and maternal tissues and may involve the modulation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling activity in maternal decidual cells. In this report, we studied implantation in Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) mice, which lack the PI3K signaling antagonist gene Pten in myometrial and stromal/decidual cells. Primiparous Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) mice were found to be subfertile because of increased fetal mortality at e11.5. Histopathological analyses revealed a failure of decidual regression in these mice, accompanied by reduced or absent invasion of fetal trophoblast glycogen cells and giant cells, abnormal development of the placental labyrinth, and frequent apparent intrauterine fetal growth restriction. Unexpectedly, the loss of phosphate and tensin homolog deleted on chromosome 10 (PTEN) expression in Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) decidual cells was not accompanied by a detectable increase in AKT phosphorylation or altered expression or activation of PI3K/AKT downstream effectors such as mammalian target of rapamycin or glycogen synthase kinase-3?. Terminal deoxynucleotidyl transferase-mediated nick end labeling and bromodeoxyuridine incorporation analyses attributed to the lack of decidual regression mainly to decreased apoptosis in Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) decidual cells, rather than to increased proliferation. Remodeling of the maternal vasculature was delayed in Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) uteri at e11.5, as evidenced by persistence of vascular smooth muscle and decreased infiltration of uterine natural killer cells. In addition, thickening of the myometrium and disorganization of the muscle fibers were observed before and throughout gestation. Almost all Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) mice failed to carry a second litter to term, apparently attributable to endometrial hyperplasia and uterine infections. Together, these data demonstrate novel roles of PTEN in the mammalian uterus and its requirement for proper trophoblast invasion and decidual regression.

Project description:Inadequate or inappropriate implantation and placentation during the establishment of human pregnancy is thought to lead to first trimester miscarriage, placental insufficiency and other obstetric complications. To create the placental blood supply, specialized cells, the 'extravillous trophoblast' (EVT) invade through the differentiated uterine endometrium (the decidua) to engraft and remodel uterine spiral arteries. We hypothesized that decidual factors would regulate EVT function by altering the production of EVT membrane and secreted factors. We used a proteomics approach to identify EVT membrane and secreted proteins regulated by decidual cell factors. Human endometrial stromal cells were decidualized in vitro by treatment with estradiol (10(-8) M), medroxyprogesterone acetate (10(-7) M) and cAMP (0.5 mM) for 14 days. Conditioned media (CM) was collected on day 2 (non-decidualized CM) and 14 (decidualized CM) of treatment. Isolated primary EVT cultured on Matrigel™ were treated with media control, non-decidualized or decidualized CM for 16 h. EVT CM was fractionated for proteins <30 kDa using size-exclusion affinity nanoparticles (SEAN) before trypsin digestion and HPLC-MS/MS. 43 proteins produced by EVT were identified; 14 not previously known to be expressed in the placenta and 12 which had previously been associated with diseases of pregnancy including preeclampsia. Profilin 1, lysosome associated membrane glycoprotein 1 (LAMP1), dipeptidyl peptidase 1 (DPP1/cathepsin C) and annexin A2 expression by interstitial EVT in vivo was validated by immunhistochemistry. Decidual CM regulation in vitro was validated by western blotting: decidualized CM upregulated profilin 1 in EVT CM and non-decidualized CM upregulated annexin A2 in EVT CM and pro-DPP1 in EVT cell lysate. Here, non-decidualized factors induced protease expression by EVT suggesting that non-decidualized factors may induce a pro-inflammatory cascade. Preeclampsia is a pro-inflammatory condition. Overall, we have demonstrated the potential of a proteomics approach to identify novel proteins expressed by EVT and to uncover the mechanisms leading to disease states.

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Prednisolone Alters Endometrial Decidual Cells and Affects Decidual-Trophoblast Interactions.

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