Regulation and Function of Laminin A5 during Mouse and Human Decidualization.
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ABSTRACT:
SUBMITTER: Yang ZS
PROVIDER: S-EPMC8745792 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Decidualization is essential to rodent and primate pregnancy. Senescence is increased during decidualization. Failure of senescence clearance during decidualization will cause pregnancy abnormality. Caveolin-1 is located in plasmalemmal caveolae and involved in senescence. However, whether caveolin-1 is involved in decidualization remains undefined. In this study, we examined the expression, regulation and function of Caveolin-1 during mouse early pregnancy and under mouse and human in vitro decidualization. From days 1 to 8 of pregnancy, Caveolin-1 signals are mainly located in endothelium and myometrium. Estrogen stimulates Caveolin-1 expression in endothelium. Deficiency of estrogen receptor α significantly promotes Caveolin-1 level in uterine stromal cells. Progesterone upregulates Caveolin-1 expression in luminal epithelium. During mouse in vitro decidualization, Caveolin-1 is significantly increased. However, Caveolin-1 is obviously decreased during human in vitro decidualization. Caveolin-1 overexpression and siRNA suppress and upregulate IGFBP1 expression under in vitro decidualization, respectively. Blastocysts-derived tumor necrosis factor α (TNFα) and human Chorionic Gonadotropin (hCG) regulate Caveolin-1 in mouse and human decidual cells, respectively. Caveolin-1 levels are also regulated by high glucose and insulin. In conclusion, a low level of Caveolin-1 should be beneficial for human decidualization.
| S-EPMC8998724 | biostudies-literature
Project description:BackgroundPlasma kisspeptin levels dramatically increased during the first trimester of human pregnancy, which is similar to pregnancy specific glycoprotein-human chorionic gonadotropin. However, its particular role in the implantation and decidualization has not been fully unraveled. Here, the study was conducted to investigate the expression and function of kisspeptin in mouse uterus during early pregnancy and decidualization.Methodology/principal findingsQuantitative PCR results demonstrated that Kiss1 and GPR54 mRNA levels showed dynamic increase in the mouse uterus during early pregnancy and artificially induced decidualization in vivo. KISS-1 and GPR54 proteins were spatiotemporally expressed in decidualizing stromal cells in intact pregnant females, as well as in pseudopregnant mice undergoing artificially induced decidualization. In the ovariectomized mouse uterus, the expression of Kiss1 mRNA was upregulated after progesterone or/and estradiol treatment. Moreover, in a stromal cell culture model, the expression of Kiss1 and GPR54 mRNA gradually rise with the progression of stromal cell decidualization, whereas the attenuated expression of Kiss1 using small interfering RNA approaches significantly blocked the progression of stromal cell decidualization.Conclusionour results demonstrated that Kiss1/GPR54 system was involved in promoting uterine decidualization during early pregnancy in mice.
| S-EPMC4022638 | biostudies-literature
Project description:Abstract Early growth response gene 1 (Egr1), a zinc finger transcriptional factor, plays an important role in regulating cell proliferation, differentiation and angiogenesis. Current data have shown that Egr1 is involved in follicular development, ovulation, luteinization and placental angiogenesis. However, the expression, regulation and function of Egr1 in mouse uterus during embryo implantation and decidualization are poorly understood. Here we showed that Egr1 was strongly expressed in the subluminal stroma surrounding the implanting blastocyst on day 5 of pregnancy. Injection of Egr1 siRNA into the mouse uterine horn could obviously reduce the number of implanted embryos and affect the uterine vascular permeability. Further study found that Egr1 played a role through influencing the expression of cyclooxygenase-2 (Cox-2), microsomal prostaglandin E synthase 1 (mPGES-1), vascular endothelial growth factor (Vegf), transformation related protein 53 (Trp53) and matrix metallopeptidase 9 (Mmp9) genes in the process of mouse embryo implantation. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) might direct the expression of Egr1 in the uterine stromal cells. Under in vivo and in vitro artificial decidualization, Egr1 expression was significantly decreased. Overexpression of Egr1 downregulated the expression of decidual marker decidual/trophoblast PRL-related protein (Dtprp) in the uterine stromal cells, while inhibition of Egr1 upregulated the expression of Dtprp under in vitro decidualization. Estrogen and progesterone could regulate the expression of Egr1 in the ovariectomized mouse uterus and uterine stromal cells. These results suggest that Egr1 may be essential for embryo implantation and decidualization.
| S-EPMC4614544 | biostudies-literature
Project description:IntroductionHigh-mobility group box 1 (HMGB1) is a non-histone nuclear protein and can be extracellularly secreted to induce sterile inflammation. Although uterine deletion of HMGB1 causes implantation and decidualization defects, how secreted HMGB1 is involved in mouse early pregnancy is still unknown.MethodsMouse models, mouse primary endometrial cells and human endometrial cell lines were used in this study. Both immunofluorescence and Western blot were performed to show the localization and relative level of HMGB1 and acetylated HMGB1, respectively. Relative mRNA levels were analyzed by real time RT-PCR.ResultsThe secreted HMGB1 was detected in uterine lumen fluid in mouse periimplantation uterus. There is an obvious difference for secreted HMGB1 levels in uterine fluid between day 4 of pregnancy and day 4 of pseudopregnancy, suggesting the involvement of blastocysts during HMGB1 secretion. Trypsin is clearly detected in mouse blastocyst cavity and in the supernatant of cultured blastocysts. Trypsin significantly stimulates HB-EGF production through activating PAR2 and ADAM17. Uterine injection of PAR2 inhibitor into day 4 pregnant mice significantly reduces the number of implantation sites. HB-EGF released from luminal epithelium can induce mouse in vitro decidualization. The conditioned medium collected from trypsin-treated luminal epithelium is able to induce in vitro decidualization, which is suppressed by EGFR inhibitor. Intrauterine injection of glycyrrhizin (HMGB1 inhibitor) can significantly inhibit mouse embryo implantation. We also showed that exogenous HMGB1 released from human epithelial cells are able to induce human in vitro decidualization.ConclusionTrypsin can induce decidualization of stromal cells via PAR2-HMGB1-ADAM17-HB-EGF from luminal epithelium.
| S-EPMC9905834 | biostudies-literature
Project description:Polyploid decidual cells are specifically differentiated cells during mouse uterine decidualization. However, little is known about the regulatory mechanism and physiological significance of polyploidization in pregnancy. Here we report a novel role of E2F8 in the polyploidization of decidual cells in mice. E2F8 is highly expressed in decidual cells and regulated by progesterone through HB-EGF/EGFR/ERK/STAT3 signaling pathway. E2F8 transcriptionally suppresses CDK1, thus triggering the polyploidization of decidual cells. E2F8-mediated polyploidization is a response to stresses which are accompanied by decidualization. Interestingly, polyploidization is not detected during human decidualization with the down-regulation of E2F8, indicating differential expression of E2F8 may lead to the difference of decidual cell polyploidization between mice and humans.
| S-EPMC4614110 | biostudies-literature
Project description:Vaginal bleeding and subchorionic hematomas are associated with increased risk of both early and late pregnancy loss. Thrombin generation may play a pivotal role in the development of these complications. To determine the effects of thrombin on human endometrial stromal cells (hESCs), cells were treated with thrombin at baseline or during decidualization with cyclic adenosine monophosphate (cAMP)+medroxyprogesterone acetate (MPA). Next-generation RNA sequencing revealed that markers of decidualization (IGF-1, IGFBP-1, and prolactin [PRL]) were induced after the initiation of decidualization, whereas thrombin suppressed insulin-like growth factor ( IGF)-1, Insulin-like growth factor binding protein ( IGFBP)-1, and PRL gene expression at baseline and during decidualization. These effects were mediated through protease activated receptor (PAR)-1- and PAR-1-independent pathways. Thrombin decreased the secretion of a key marker of decidualization (PRL), altered the morphological transformation of decidualizing hESCs, and activated genes involved in matrix degradation and proinflammatory chemokines ( Interleukin-8 and Interleukin-6). Genes encoding factors important for matrix stability ( Col1α1, LOX) were suppressed. We suggest that intrauterine bleeding and generation of thrombin accentuates leukocyte extravasation and endometrial inflammation, impairs decidualization, and endometrial support of early pregnancy.
| S-EPMC6728565 | biostudies-literature
Project description:Infertility is constantly increasing in Canada, where 16% of Canadian couples are experiencing difficulty conceiving. It is thought that infertility can emanate from the dysregulated communication between the embryo and the maternal endometrium. In order to allow for this window of implantation to be open at the right moment, endometrial stromal cells proliferate and differentiate by a mechanism called decidualization. Intracellular and molecular mechanisms involved in the regulation of apoptosis and cell proliferation during decidualization of the endometrium are yet to be fully understood. It has been well demonstrated previously that Akt is importantly involved in cell survival and glycogen synthesis. Akt1, Akt2 and Akt3 isoforms have distinct physiological roles; this could also be the case during decidualization and pregnancy. The aim of this study is to investigate the regulation of PI3K/Akt pathway during the decidualization process of endometrial stromal cells. Expression of Akt isoforms, Akt activity (phospho-Akt), pIκB and substrates of Akt during decidualization were measured. To our knowledge, these results are the first to suggest a decrease in levels of Akt isoforms as well as a downregulation of Akt activity in the process of decidualization of human endometrial stromal cells. We also uncovered that decidualization induced nuclear localization of p65 through the phosphorylation of IκB, its inhibitory subunit; however, Par-4, a recently uncovered regulator of cell differentiation, was displaced from the nucleus upon decidualization. Our results also suggest that HIESC cells exhibit decreased motility during decidualization and that PI3K pathway inhibition could be involved in this process. Finally, we demonstrate that specific Akt isoforms present unique effects on the successful induction of decidualization. Further analyses will involve investigations to understand the precise signaling mechanisms by which this pathway is regulated.
| S-EPMC5419658 | biostudies-literature
Project description:During decidualization in rodents, uterine stromal cells undergo extensive reprogramming to differentiate into distinct cell types, forming primary decidual zones (PDZs), secondary decidual zones (SDZs), and layers of undifferentiated stromal cells. The formation of secondary decidual zones is accompanied by extensive angiogenesis. During early pregnancy, besides ovarian estrogen, de novo synthesis of estrogen in the uterus is essential for the progress of decidualization. However, the molecular mechanisms are not fully understood. Studies have shown that Cystatin B (Cstb) is highly expressed in the decidual tissue of the uterus, but the regulation and mechanism of Cstb in the process of decidualization have not been reported. Our results showed that Cstb was highly expressed in mouse decidua and artificially induced deciduoma via in situ hybridization and immunofluorescence. Estrogen stimulates the expression of Cstb through the Estrogen receptor (ER)α. Moreover, in situ synthesis of estrogen in the uterus during decidualization regulates the expression of Cstb. Silencing the expression of Cstb affects the migration ability of stromal cells. Knockdown Cstb by siRNA significantly inhibits the expression of Dtprp, a marker for mouse decidualization. Our study identifies a novel estrogen target, Cstb, during decidualization and reveals that Cstb may play a pivotal role in angiogenesis during mouse decidualization via the Angptl7.
| S-EPMC9820648 | biostudies-literature
Project description:Background/aimPatients with polycystic ovary syndrome (PCOS), characterized by anovulation, hyperandrogenemia and polycystic ovaries, are still vulnerable to undergo recurrent pregnancy loss and premature labor even though the ovulatory process is pharmacologically recovered. However, its potential mechanism remains unknown. Thus, our aim was to investigate the effect and mechanism of hyperandrogenemia and flutamide (a non-steroidal anti-androgen) on the embryo implantation and pregnancy during mid-pregnancy.MethodsWe used a mouse model in which PCOS-like hyperandrogenemia was induced by subcutaneous injection of testosterone propionate. In this model, we observed the effect of hyperandrogenemia and flutamide on the decidualization, angiogenesis and uNK cells by methods of immunohistochemistry, quantitative PCR, western blotting and Dolichos biflorus agglutinin (DBA) lectin staining.ResultsTestosterone and flutamide treatment did not significantly influence the numbers of implanted embryo compared with the control group. However, different doses of testosterone significantly increased the ratio of resorbed /implanted embryo, decreased the level of prl8a2 mRNA and cyclin D3 protein, inhibited the uterine angiogenesis and reduced the numbers of uNK cells, but combined treatment with flutamide markedly decreased the resorbed embryos, increased expressions of prl8a2 mRNA and cyclin D3 protein and angiogenesis and numbers of uNK cells.ConclusionFlutamide treatment can efficiently ameliorate the hyperandrogenemia-induced the disorders in aspects of decidualization, angiogenesis and uNK cells, which further improve the poor endometrial receptivity in PCOS patients.
| S-EPMC6544220 | biostudies-literature
Project description:The steroid hormones 17?-estradiol and progesterone are critical regulators of endometrial stromal cell differentiation, known as decidualization, which is a prerequisite for successful establishment of pregnancy. The present study using primary human endometrial stromal cells (HESCs) addressed the role of estrogen receptor-? (ESR1) in decidualization. Knockdown of ESR1 transcripts by RNA interference led to a marked reduction in decidualization of HESCs. Gene expression profiling at an early stage of decidualization indicated that ESR1 negatively regulates several cell cycle regulatory factors, thereby suppressing the proliferation of HESCs as these cells enter the differentiation program. ESR1 also controls the expression of WNT4, FOXO1, and progesterone receptor (PGR), well-known mediators of decidualization. Whereas ESR1 knockdown strongly inhibited the expression of FOXO1 and WNT4 transcripts within 24 hours of the initiation of decidualization, PGR expression remained unaffected at this early time point. Our study also revealed a major role of cAMP signaling in influencing the function of ESR1 during decidualization. Using a proteomic approach, we discovered that the cAMP-dependent protein kinase A (PKA) phosphorylates Mediator 1 (MED1), a subunit of the mediator coactivator complex, during HESC differentiation. Using immunoprecipitation, we demonstrated that PKA-phosphorylated MED1 interacts with ESR1. The PKA-dependent phosphorylation of MED1 was also correlated with its enhanced recruitment to estrogen-responsive elements in the WNT4 gene. Knockdown of MED1 transcripts impaired the expression of ESR1-induced WNT4 and FOXO1 transcripts and blocked decidualization. Based on these findings, we conclude that modulation of ESR1-MED1 interactions by cAMP signaling plays a critical role in human decidualization.
| S-EPMC4771698 | biostudies-literature