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Lois A Salamonsen - One of the best experts on this subject based on the ideXlab platform.
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a distinct cohort of the tgfβ superfamily members expressed in human endometrium regulate Decidualization
Human Reproduction, 2008Co-Authors: C Stoikos, Lois A Salamonsen, Craig A Harrison, Evdokia DimitriadisAbstract:BACKGROUND Successful blastocyst implantation requires the differentiation of human endometrial stromal cells (HESC), a process known as Decidualization. Activin A, a transforming growth factor beta (TGFbeta) superfamily member, enhances HESC Decidualization and localizes to decidual cells in human endometrium. Other TGFbeta superfamily members, including BMP2, BMP4, BMP7, GDF5, GDF8, GDF11, TGFbetas and Nodal, may also play a role during Decidualization. This study aimed to identify these TGFbeta family members in human endometrium, and to determine whether they are involved in human Decidualization. METHODS Protein localization of TGFbeta family members was examined in secretory phase human endometrium and first trimester decidua by immunohistochemistry. mRNA expression was examined in HESC. Activin inhibitors (Activin-M108A/SB431542) with differing specificities for the other TGFbeta members under consideration were applied during HESC Decidualization in vitro. The secretion levels of potential TGFbeta superfamily members were measured during Decidualization, and recombinant proteins added to examine their effect. RESULTS This study has identified BMP2, BMP4, BMP7, GDF5, GDF8 and GDF11 but not Nodal in secretory phase human endometrium, but only BMP2, GDF5 and TGFbeta1 protein were detected in decidual cells. All ligands except Nodal were expressed by cultured HESC. Both inhibitors significantly reduced Decidualization validating the role of activin, but potentially also other TGFbeta members, during Decidualization. BMP2 and TGFbeta1 secretion increased during HESC decidualisation and exogenous administration of these proteins significantly enhanced Decidualization in vitro. CONCLUSIONS Like activin, BMP2 and TGFbeta1 are likely to be involved in HESC Decidualization. This is the first study to identify and localize BMP4, BMP7, GDF5, GDF8 and GDF11 in secretory phase human endometrium. Understanding the factors critical for the implantation process is needed for improving fertility and pregnancy outcomes.
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activin a and inhibin a differentially regulate human uterine matrix metalloproteinases potential interactions during Decidualization and trophoblast invasion
Endocrinology, 2006Co-Authors: Jock K Findlay, Paul G Farnworth, Rebecca L Jones, David Robertson, Euan M Wallace, Lois A SalamonsenAbstract:Embryo implantation and trophoblast invasion are tightly regulated processes, involving sophisticated communication between maternal decidual and fetal trophoblast cells. Decidualization is a prerequisite for successful implantation and is promoted by a number of paracrine agents, including activin A. To understand the downstream mechanisms of activin-promoted Decidualization, the effects of activin on matrix metalloproteinases (MMPs) (important mediators of Decidualization) were investigated. Activin A stimulated endometrial production of proMMPs-2, -3, -7, -9, and active MMP-2. In contrast, inhibin A was a potent inhibitor of proMMP-2, and antagonized the effect of activin on MMPs. Activin is up-regulated with Decidualization, and MMPs-2, -3, and -9 increase in parallel. Furthermore, proMMP-2 production is stimulated when Decidualization is accelerated with activin, and suppressed when activin is neutralized, attenuating Decidualization. These data support that activin A promotes Decidualization through up-regulating MMPs. Previous in vitro evidence proposes further roles for activin and MMPs in promoting trophoblast invasion; therefore, we examined their interrelationships in early human implantation sites. MMPs-7 and -9 were produced by static cytotrophoblast subpopulations, whereas MMP-2 was strikingly up-regulated in invasive extravillous cytotrophoblasts (EVT). Maternal decidua is the primary source of activin, where a role in stimulating MMP-2 in iEVTs can be envisaged. Inhibin was absent from cytotrophoblast populations, except for a dramatic up-regulation in endovascular EVT plugs, coinciding with a down-regulation of MMP-2. This suggests that inhibin may have a role in the cessation of vascular invasion. These data support that activin, via effects on MMPs, is an important factor in the maternal-fetal dialog regulating implantation.
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activin a and inhibin a differentially regulate human uterine matrix metalloproteinases potential interactions during Decidualization and trophoblast invasion
Endocrinology, 2006Co-Authors: Rebecca L Jones, Jock K Findlay, Paul G Farnworth, David Robertson, Euan M Wallace, Lois A SalamonsenAbstract:Embryo implantation and trophoblast invasion are tightly regulated processes, involving sophisticated communication between maternal decidual and fetal trophoblast cells. Decidualization is a prerequisite for successful implantation and is promoted by a number of paracrine agents, including activin A. To understand the downstream mechanisms of activin-promoted Decidualization, the effects of activin on matrix metalloproteinases (MMPs) (important mediators of Decidualization) were investigated. Activin A stimulated endometrial production of proMMPs-2, -3, -7, -9, and active MMP-2. In contrast, inhibin A was a potent inhibitor of proMMP-2, and antagonized the effect of activin on MMPs. Activin is up-regulated with Decidualization, and MMPs-2, -3, and -9 increase in parallel. Furthermore, proMMP-2 production is stimulated when Decidualization is accelerated with activin, and suppressed when activin is neutralized, attenuating Decidualization. These data support that activin A promotes Decidualization through...
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requirement for proprotein convertase 5 6 during Decidualization of human endometrial stromal cells in vitro
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Hidetaka Okada, G Nie, Lois A SalamonsenAbstract:Decidualization of endometrial stromal cells (ESCs) is critical for embryo implantation and maintenance of pregnancy. Proprotein convertase (PC) 5/6 is suggested to play an important role in the processes of stromal cell Decidualization and embryo implantation in the mouse. PC5/6 is a member of the PC family responsible for processing precursor proteins to their active forms by selective proteolysis. In this study, we investigated the regulation of PC5/6 mRNA and protein expression in human ESCs during Decidualization in vitro. Real-time PCR analyses revealed a significant increase in PC5/6 mRNA levels in ESCs treated with 17β-estradiol (E2) plus medroxy-progesterone acetate during Decidualization. On the other hand, E2 alone did not increase PC5/6 mRNA expression. Intense PC5/6 immunoreactivity was observed in the cytoplasm of E2 plus medroxy-progesterone acetate-treated ESCs (decidualized ESCs) compared with E2-treated ESCs on d 12 of culture (nondecidualized ESCs). This PC5/6 immunoreactivity was aboli...
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activin a promotes human endometrial stromal cell Decidualization in vitro
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Rebecca Jones, Lois A Salamonsen, J K FindlayAbstract:Decidualization of the endometrium is critical for implantation and placental development. Stromal cells differentiate causing widespread tissue remodeling. The mechanisms involved are unknown, although a number of known paracrine factors play contributory roles. From its known actions on cell differentiation and remodeling, we hypothesized that activin A regulates Decidualization. Stromal cells produce activinβ A subunits with the onset of Decidualization, and these cells coexpress activin receptors. Utilizing an in vitro model of stromal cell Decidualization, we demonstrate that high concentrations of dimeric activin A are produced by decidual cells. Addition of activin A to cells undergoing Decidualization resulted in a dose-dependent increase in PRL production, an established marker of Decidualization. This response was inhibited by co-treatment with follistatin. Neutralization of endogenous activins significantly reduced the decidual response. This is the first report of dimeric activin A production ...
Zengming Yang - One of the best experts on this subject based on the ideXlab platform.
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the high concentration of progesterone is harmful for endometrial receptivity and Decidualization
Scientific Reports, 2018Co-Authors: Yuxiang Liang, Xiaohuan Liang, Li Liu, Zhiyong Jin, Zengming YangAbstract:Progesterone is required for the establishment and maintenance of mammalian pregnancy and widely used for conservative treatment of luteal phase deficiency in clinics. However, there are limited solid evidences available for the optimal timing and dose of progesterone therapy, especially for the possible adverse effects on implantation and Decidualization when progesterone is administrated empirically. In our study, mouse models were used to examine effects of excess progesterone on embryo implantation and Decidualization. Our data indicate that excess progesterone is not only harmful for mouse implantation, but also impairs mouse Decidualization. In excess progesterone-treated mice, the impaired LIF/STAT3 pathway and dysregulated endoplasmic reticulum stress may lead to the inhibition of embryo implantation and Decidualization. It is possible that the decrease in birth weight of excess progesterone-treated mice is due to a compromised embryo implantation and Decidualization. Furthermore, excess progesterone compromises in vitro Decidualization of human endometrial stromal cells.
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De novo synthesis of sphingolipids is essential for Decidualization in mice.
Theriogenology, 2017Co-Authors: Nai-zheng Ding, Ru-juan Zuo, Jie Liu, Zengming YangAbstract:Sphingolipids play multiple roles in membrane structure, signal transduction, stress responses, neural development and immune reaction. The rate of de novo synthesis pathway of sphingolipids is regulated by two key enzymes, serine palmitoyltransferase (SPT), and ketoreductase (Kds). Here, we find that the mRNA levels of three subunits of the SPT holoenzyme (Sptlc1, Sptlc2, and Ssspta) are significantly up-regulated in mouse uterine stromal cells during Decidualization. The expression of Kds, which reduces 3-keto-dihydrosphingosine to dihydrosphingosine, is co-localized with Sptlc1 in mouse uteri during early pregnancy. Moreover, l-Cycloserine, a specific inhibitor of SPT, can significantly decrease the weight and number of implantation sites, and impede the Decidualization process in mouse uterine stromal cells, suggesting that blockage of de novo sphingolipid synthesis may cause defective Decidualization and early pregnancy loss in mice. In addition, this study also shows progesterone (P4) can stimulate the expression of both Sptlc2 and Ssspta in mouse uterus. Therefore, our study shows that de novo synthesis of sphingolipids is necessary in implantation and plays a key role in Decidualization of mouse.
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hb egf regulates prss56 expression during mouse Decidualization via egfr erk egr2 signaling pathway
Journal of Endocrinology, 2017Co-Authors: Jie Liu, Fei Gao, Yuefang Liu, Haiting Dou, Jiaqi Yan, Zongmin Fan, Zengming YangAbstract:Embryo implantation and Decidualization are key steps for successful reproduction. Although numerous factors have been identified to be involved in embryo implantation and Decidualization, the mechanisms underlying these processes are still unclear. Based on our preliminary data, Prss56, a trypsin-like serine protease, is strongly expressed at implantation site in mouse uterus. However, the expression, regulation and function of Prss56 during early pregnancy are still unknown. In mouse uterus, Prss56 is strongly expressed in the subluminal stromal cells at implantation site on day 5 of pregnancy compared to inter-implantation site. Under delayed implantation, Prss56 expression is undetected. After delayed implantation is activated by estrogen, Prss56 is obviously induced at implantation site. Under artificial Decidualization, Prss56 signal is seen at the primary decidual zone at the initial stage of artificial Decidualization. When stromal cells are induced for in vitro Decidualization, Prss56 expression is significantly elevated. Dtprp expression under in vitro Decidualization is suppressed by Prss56 siRNA. In cultured stromal cells, HB-EGF markedly stimulates Prss56 expression through EGFR/ERK pathway. Based on promoter analysis, we also showed that Egr2 is involved in Prss56 regulation by HB-EGF. Collectively, Prss56 expression at implantation site is modulated by HB-EGF/EGFR/ERK signaling pathway and involved in mouse Decidualization.
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Differential Expression of Interleukin 1 Receptor Type II During Mouse
2016Co-Authors: Xiu-hong Zhang, Tongsong Wang, Wei Lei, Zhen Tian, Zhen-ao Zhao, Zengming YangAbstract:Interleukin 1 (IL-1) is one of the most potent proinflammatory cytokines possessing a wide spectrum of inflammatory, metabolic, hemopoietic, and immunologic properties. In addition, the IL-1 system has been considered relevant in regulating communication between the blastocyst and the endometrium. Interleukin 1 receptor type II (IL1R2) acts as a negative regulator for IL-1 actions and has been termed a ‘‘decoy receptor.’ ’ The aim of this study was to determine the expression pattern of IL1R2 gene in mouse uterus during the early pregnancy. Both in situ hybridization and immunohistochemistry were performed to examine the spatial localization of IL1R2 expression in mouse uteri. Real-time quantitative polymerase chain reaction analyses were used to quantify Il1r2 messenger RNA (mRNA) level under in vivo and in vitro artificial Decidualization. By transfecting Il1r2 gene in cultured stro-mal cells from day 4 pregnant mice, we detected the expression of Dtprp, a well-known marker for Decidualization. Our results showed that IL1R2 gene expression was mainly localized in decidual cells close to the implanting embryo during days 5 to 8 of pregnancy. Under in vivo and in vitro artificial Decidualization, Il1r2 was significantly upregulated. Dtprp mRNA expression was also upregulated by Il1r2 overexpression. Our data suggest that IL1R2 may play an important role during mouse Decidualization
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non coding rna linc00473 mediates Decidualization of human endometrial stromal cells in response to camp signaling
Scientific Reports, 2016Co-Authors: Xiaohuan Liang, Zengming Yang, Yuefang Liu, Zongmin Fan, Wenbo Deng, Yuxiang Liang, Jilong Liu, Aiguo Sha, Honglu DiaoAbstract:Decidualization is an essential step in the establishment of pregnancy. However, the functional contributions of long intergenic noncoding RNAs (LincRNAs) to Decidualization have not been explored. To explore the regulation and role of LincRNAs during human Decidualization, human endometrial stromal cells (HESCs) are induced to undergo in vitro Decidualization by treating with estradiol-17β, db-cAMP and medroxyprogesterone acetate. LINC00473 (LINC473) expression is highly induced in HESCs after decidual stimulus. We found that cAMP-PKA pathway regulates the expression of LINC473 through IL-11-mediated STAT3 phosphorylation. RNA interference-mediated down-regulation of LINC473 inhibits in vitro Decidualization. These results suggested that LINC473 might be functionally required for human Decidualization. This is the first report demonstrating the presence of LincRNA during human Decidualization.
Rebecca L Jones - One of the best experts on this subject based on the ideXlab platform.
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activin a and inhibin a differentially regulate human uterine matrix metalloproteinases potential interactions during Decidualization and trophoblast invasion
Endocrinology, 2006Co-Authors: Jock K Findlay, Paul G Farnworth, Rebecca L Jones, David Robertson, Euan M Wallace, Lois A SalamonsenAbstract:Embryo implantation and trophoblast invasion are tightly regulated processes, involving sophisticated communication between maternal decidual and fetal trophoblast cells. Decidualization is a prerequisite for successful implantation and is promoted by a number of paracrine agents, including activin A. To understand the downstream mechanisms of activin-promoted Decidualization, the effects of activin on matrix metalloproteinases (MMPs) (important mediators of Decidualization) were investigated. Activin A stimulated endometrial production of proMMPs-2, -3, -7, -9, and active MMP-2. In contrast, inhibin A was a potent inhibitor of proMMP-2, and antagonized the effect of activin on MMPs. Activin is up-regulated with Decidualization, and MMPs-2, -3, and -9 increase in parallel. Furthermore, proMMP-2 production is stimulated when Decidualization is accelerated with activin, and suppressed when activin is neutralized, attenuating Decidualization. These data support that activin A promotes Decidualization through up-regulating MMPs. Previous in vitro evidence proposes further roles for activin and MMPs in promoting trophoblast invasion; therefore, we examined their interrelationships in early human implantation sites. MMPs-7 and -9 were produced by static cytotrophoblast subpopulations, whereas MMP-2 was strikingly up-regulated in invasive extravillous cytotrophoblasts (EVT). Maternal decidua is the primary source of activin, where a role in stimulating MMP-2 in iEVTs can be envisaged. Inhibin was absent from cytotrophoblast populations, except for a dramatic up-regulation in endovascular EVT plugs, coinciding with a down-regulation of MMP-2. This suggests that inhibin may have a role in the cessation of vascular invasion. These data support that activin, via effects on MMPs, is an important factor in the maternal-fetal dialog regulating implantation.
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activin a and inhibin a differentially regulate human uterine matrix metalloproteinases potential interactions during Decidualization and trophoblast invasion
Endocrinology, 2006Co-Authors: Rebecca L Jones, Jock K Findlay, Paul G Farnworth, David Robertson, Euan M Wallace, Lois A SalamonsenAbstract:Embryo implantation and trophoblast invasion are tightly regulated processes, involving sophisticated communication between maternal decidual and fetal trophoblast cells. Decidualization is a prerequisite for successful implantation and is promoted by a number of paracrine agents, including activin A. To understand the downstream mechanisms of activin-promoted Decidualization, the effects of activin on matrix metalloproteinases (MMPs) (important mediators of Decidualization) were investigated. Activin A stimulated endometrial production of proMMPs-2, -3, -7, -9, and active MMP-2. In contrast, inhibin A was a potent inhibitor of proMMP-2, and antagonized the effect of activin on MMPs. Activin is up-regulated with Decidualization, and MMPs-2, -3, and -9 increase in parallel. Furthermore, proMMP-2 production is stimulated when Decidualization is accelerated with activin, and suppressed when activin is neutralized, attenuating Decidualization. These data support that activin A promotes Decidualization through...
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expression of activin receptors follistatin and betaglycan by human endometrial stromal cells consistent with a role for activins during Decidualization
Molecular Human Reproduction, 2002Co-Authors: Rebecca L Jones, Lois A Salamonsen, Yi Chen Zhao, Jeanfranciois Ethier, Ann E Drummond, J K FindlayAbstract:Decidualization of the human endometrium is critical for implantation, but the mechanisms involved are largely unknown. Activin subunits are expressed in endometrium during Decidualization. From its known actions in cell differentiation and tissue remodelling, we hypothesized that activin A is involved in the paracrine regulation of Decidualization. We examined the expression of activin receptors (ActRs) by semi-quantitative and real-time RT-PCR. mRNA for all ActR subtypes (Ia, Ib, IIa and IIb) was detected in endometrium, with maximal expression in the early secretory phase and in early pregnancy. ActR protein was localized exclusively to stromal and endothelial cells. This expression pattern was confirmed by in-situ hybridization. Activin bioavailability is locally regulated by its binding protein, follistatin, and also by the antagonist, inhibin. Inhibin competition for ActRII binding is enhanced by the binding protein, betaglycan. Follistatin and betaglycan were also detected in the endometrium, localized to stromal and epithelial cells. This co-expression of activin subunits, receptors and binding proteins indicates that stromal cells are capable of responding to activin, and that there is tight local regulation of activin action within the endometrium. As activin production is up-regulated in decidual cells, this provides further evidence for an involvement of activins during stromal cell Decidualization.
Asgerally T Fazleabas - One of the best experts on this subject based on the ideXlab platform.
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physiologic events of embryo implantation and Decidualization in human and non human primates
International Journal of Molecular Sciences, 2020Co-Authors: Maria Ariadna Ochoabernal, Asgerally T FazleabasAbstract:Reproduction is a fundamental process for the preservation of the human species. This process requires a sequence of orchestrated events that are necessary for a successful pregnancy. Two of the most critical steps in the establishment of human pregnancy are implantation and Decidualization, which are required for maternal interactions with the developing embryo. This review primarily highlights the physiological aspects of these two events and the adverse pregnancy outcomes from defective implantation and Decidualization. The focus of this review is to provide a general concept of the mechanisms involved during the window of implantation, description of components involved in the process and possible pathologies that could disrupt the embryo implantation and Decidualization and specifically as it applies to women and non-human primates.
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loss of hdac3 results in nonreceptive endometrium and female infertility
Science Translational Medicine, 2019Co-Authors: Tae Hoon Kim, Jungyoon Yoo, Kyung Chul Choi, Jung Ho Shin, Richard E Leach, Asgerally T Fazleabas, Steven L YoungAbstract:Endometriosis is a disease in which tissue that normally grows inside the uterus grows outside the uterus and causes chronic pelvic pain and infertility. However, the exact mechanisms of the pathogenesis of endometriosis-associated infertility are unknown. Epigenetic dysregulation has recently been implicated in infertility. Here, we report a reduction of histone deacetylase 3 (HDAC3) protein amounts in eutopic endometrium of infertile women with endometriosis compared to a control group. To investigate the effect of HDAC3 loss in the uterus, we generated mice with conditional ablation of Hdac3 in progesterone receptor (PGR)-positive cells (Pgrcre/+Hdac3f/f ; Hdac3d/d ). Loss of Hdac3 in the uterus of mice results in infertility due to implantation failure and Decidualization defect. Expression microarray and ChIP-seq analyses identified COL1A1 and COL1A2 as direct targets of HDAC3 in both mice and humans. Reduction of HDAC3 abrogated Decidualization in a primary culture of human endometrial stromal cells (hESCs) similar to that observed in infertile patients with endometriosis. Whereas attenuation of HDAC3 resulted in p300 recruitment to Col1a1 and Col1a2 genes in the uterus of mice as well as hESCs, inhibition of p300 permitted hESCs to undergo Decidualization. Collectively, we found attenuation of HDAC3 and overexpression of collagen type I in the eutopic endometrium of infertile patients with endometriosis. HDAC3 loss caused a defect of Decidualization through the aberrant transcriptional activation of Col1a1 and Col1a2 genes in mice and COL1A1 and COL1A2 genes in humans. Our results suggest that HDAC3 is critical for endometrial receptivity and Decidualization.
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bisphenol a impairs Decidualization of human uterine stromal fibroblasts
Reproductive Toxicology, 2017Co-Authors: Mark Olson, Asgerally T Fazleabas, Jodi A FlawsAbstract:Abstract This study examined the effect of bisphenol A (BPA) exposure on human uterine stromal fibroblast cells (HuF) undergoing Decidualization. HuF cells were isolated and cultured for eight days in the presence of a Decidualization-inducing cocktail, while concurrently exposed to physiological and supra-physiologic doses of BPA (1 ng/mL, 10 ng/mL, 0.5 μg/mL, 10 μg/mL and 20 μg/mL). Decidualization markers, steroid hormone receptors and cell cycle gene expression were detected by qRT-PCR and cellular proliferation was assessed by KI-67 immunofluorescent staining and MTS assay. BPA impaired Decidualization at 10 μg/mL and 20 μg/mL, but not at lower doses. Additionally, BPA at 20 μg/mL decreased progesterone receptor and estrogen receptor-alpha compared to controls. The highest dose of BPA also reduced cellular proliferation and cyclin D2 expression compared to controls. These findings demonstrate that BPA disrupts in vitro Decidualization of uterine stromal fibroblasts by altering steroid hormone receptor expression at higher concentrations but not at lower physiological doses.
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camp response element binding 3 like protein 1 creb3l1 is required for Decidualization and its expression is decreased in women with endometriosis
Current Molecular Medicine, 2016Co-Authors: J I Ahn, Jungyoon Yoo, Asgerally T Fazleabas, Young Im Kim, Susan D Ferguson, Ji Yeon Ahn, Bruce A Lessey, T H Kim, Simon Young, Jeong Mook LimAbstract:Endometriosis is a major cause of infertility and pelvic pain, affecting more than 10% of reproductive-aged women. Progesterone resistance has been observed in the endometrium of women with this disease, as evidenced by alterations in progesterone-responsive gene and protein expression. cAMPResponse Element-Binding 3-like protein 1 (Creb3l1) has previously been identified as a progesterone receptor (PR) target gene in mouse uterus via high density DNA microarray analysis. However, CREB3L1 function has not been studied in the context of endometriosis and uterine biology. In this study, we validated progesterone (P4) regulation of Creb3l1 in the uteri of wild-type and progesterone receptor knockout (PRKO) mice. Furthermore, we observed that CREB3L1 expression was significantly higher in secretory phase human endometrium compared to proliferative phase and that CREB3L1 expression was significantly decreased in the endometrium of women with endometriosis. Lastly, by transfecting CREB3L1 siRNA into cultured human endometrial stromal cells (hESCs) prior to hormonal induction of in vitro Decidualization, we showed that CREB3L1 is required for the Decidualization process. Interestingly, phosphorylation of ERK1/2, critical factor for Decidualization, was also significantly reduced in CREB3L1-silenced hESCs. It is known that hESCs from patients with endometriosis show impaired Decidualization and that dysregulation of the P4-PR signaling axis is linked to a variety of endometrial diseases including infertility and endometriosis. Therefore, these results suggest that CREB3L1 is required for Decidualization in mice and humans and may be linked to the pathogenesis of endometriosis in a P4-dependent manner.
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decreased notch pathway signaling in the endometrium of women with endometriosis impairs Decidualization
The Journal of Clinical Endocrinology and Metabolism, 2015Co-Authors: Michael R Strug, Jae Wook Jeong, Lucio Miele, Niraj Joshi, Bruce A Lessey, Steve L Young, Asgerally T FazleabasAbstract:Context: Endometriosis is a common gynecological disease affecting one in 10 women of reproductive age and is a major cause of pelvic pain and impaired fertility. Endometrial stromal cells of women with endometriosis exhibit a reduced response to in vitro Decidualization. NOTCH1 is critical for Decidualization of both mouse and human uterine stromal cells. Objective: This study aimed to determine whether Decidualization failure in women with endometriosis is a consequence of impaired Notch signaling. Setting and Design: We investigated expression levels of Notch signaling components in the endometrium of women and baboons with or without endometriosis. We identified NOTCH1-regulated genes during Decidualization of human uterine fibroblast (HuF) cells by microarray and quantified their expression levels in in vitro–decidualized endometrial stromal cells isolated from women with or without endometriosis. Results: Notch signaling receptors NOTCH1 and NOTCH4, ligands JAGGED2 and DLL4, as well as direct target...
G Nie - One of the best experts on this subject based on the ideXlab platform.
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posttranslational activation of bone morphogenetic protein 2 is mediated by proprotein convertase 6 during Decidualization for pregnancy establishment
Endocrinology, 2010Co-Authors: Sophea Heng, Belinda M Hardman, Sarah Paule, Harmeet Singh, Adam Rainczuk, Andrew N Stephens, G NieAbstract:Bone morphogenetic proteins (BMPs) require major posttranslational modifications to become biologically active. One such key modification is endoproteolytic cleavage of the initially synthesized nonactive precursor protein to release the mature ligand. Here we show in a physiological context of uterine stromal Decidualization that BMP2 cleavage is mediated by proprotein convertase 5/6 (PC6). Decidualization is a uterine remodeling event critical for embryo implantation. Deletion or knockdown of either BMP2 or PC6 inhibits Decidualization causing implantation failure and female infertility. In this study we provide biochemical and physiological evidence that PC6 proteolytically activates BMP2. We used freshly isolated primary human endometrial stromal cells and demonstrated that PC6 was the sole member of the PC family significantly up-regulated during Decidualization. The precursor form of BMP2 was reduced, whereas its active form was increased during Decidualization. Inhibition of PC6 activity inhibited ...
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175 the role of proprotein convertase 6 during Decidualization regulation of bone morphogenetic protein 2 activation
Reproduction Fertility and Development, 2009Co-Authors: Sophea Heng, Belinda M Hardman, Sarah Paule, Harmeet Singh, G NieAbstract:Proprotein convertase 5/6 (PC6), a member of the proprotein convertase (PC) family, is a critical endometrial factor for implantation. PC6 is up-regulated in the endometrium specifically at implantation in association with epithelial differentiation (in human and monkey) and stromal cell Decidualization (in the mouse, human and monkey). PC6 is the only PC member that was significantly up-regulated during Decidualization. Knockdown of PC6 inhibits Decidualization. PCs function by converting a range of important precursor proteins into their bioactive forms. One group of such proteins is the transforming growth factor beta (TGF-beta) superfamily proteins. They are first synthesized as larger biologically inactive precursors, and then are processed by PCs into their active forms. Bone morphogenetic protein 2 (BMP2) is a TGF-beta superfamily member and demonstrated to be essential for Decidualization. We hypothesized that BMP2 is one of the proteins that PC6 activates during Decidualization. Freshly isolated stromal cells from human endometrium were decidualized in culture with and without inhibition of PC6 activity. The full-length (precursor, non-active) and processed (activated) forms of BMP2 were determined in cellular lysates and media. The precursor form of BMP2 was reduced whereas the active form was increased during Decidualization. Inhibition of PC6 activity inhibited Decidualization, and this inhibition was accompanied by a total inhibition of the production of active BMP2. To further confirm the role of PC6 in activating BMP2 in Decidualization, active BMP2 was added into cells and the Decidualization arrest caused by PC6 inhibition was partially rescued. This study demonstrated that PC6 regulates Decidualization by activating molecules such as BMP2 that are essential for Decidualization.
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requirement for proprotein convertase 5 6 during Decidualization of human endometrial stromal cells in vitro
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Hidetaka Okada, G Nie, Lois A SalamonsenAbstract:Decidualization of endometrial stromal cells (ESCs) is critical for embryo implantation and maintenance of pregnancy. Proprotein convertase (PC) 5/6 is suggested to play an important role in the processes of stromal cell Decidualization and embryo implantation in the mouse. PC5/6 is a member of the PC family responsible for processing precursor proteins to their active forms by selective proteolysis. In this study, we investigated the regulation of PC5/6 mRNA and protein expression in human ESCs during Decidualization in vitro. Real-time PCR analyses revealed a significant increase in PC5/6 mRNA levels in ESCs treated with 17β-estradiol (E2) plus medroxy-progesterone acetate during Decidualization. On the other hand, E2 alone did not increase PC5/6 mRNA expression. Intense PC5/6 immunoreactivity was observed in the cytoplasm of E2 plus medroxy-progesterone acetate-treated ESCs (decidualized ESCs) compared with E2-treated ESCs on d 12 of culture (nondecidualized ESCs). This PC5/6 immunoreactivity was aboli...
