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Cell Reports May 2024The decidua plays a crucial role in providing structural and trophic support to the developing conceptus before placentation. Following embryo attachment, embryonic...
The decidua plays a crucial role in providing structural and trophic support to the developing conceptus before placentation. Following embryo attachment, embryonic components intimately interact with the decidual tissue. While evidence indicates the participation of embryo-derived factors in crosstalk with the uterus, the extent of their impact on post-implantation decidual development requires further investigation. Here, we utilize transgenic mouse models to selectively eliminate primary trophoblast giant cells (pTGCs), the embryonic cells that interface with maternal tissue at the forefront. pTGC ablation impairs decidualization and compromises decidual interferon response and lipid metabolism. Mechanistically, pTGCs release factors such as interferon kappa (IFNK) to strengthen the decidual interferon response and lipoprotein lipase (LPL) to enhance lipid accumulation within the decidua, thereby promoting decidualization. This study presents genetic and metabolomic evidence reinforcing the proactive role of pTGC-derived factors in mobilizing maternal resources to strengthen decidualization, facilitating the normal progression of early pregnancy.
PubMed: 38762885
DOI: 10.1016/j.celrep.2024.114246 -
Reproduction & Fertility Nov 2023Approximately 50% of human pregnancies humans fail, most before or during implantation. One factor contributing to pregnancy loss is abnormal glucose metabolism in the...
Approximately 50% of human pregnancies humans fail, most before or during implantation. One factor contributing to pregnancy loss is abnormal glucose metabolism in the endometrium. Glucose contributes to preimplantation embryo development, uterine receptivity, and attachment of the embryo. Across multiple species, the epithelium stores glucose as the macromolecule glycogen at estrus. This reserve is mobilized during the preimplantation period. Glucose from circulation or glycogenolysis can be secreted into the uterine lumen for use by the embryo or metabolized via glycolysis, producing ATP for the cell. The resulting pyruvate could be converted to lactate, another important nutrient for the embryo. Fructose is an important nutrient for early embryos, and the epithelium and placenta can convert glucose to fructose via the polyol pathway. The epithelium also uses glucose to glycosylate proteins, which regulates embryo attachment. In some species, decidualization of the stroma is critical to successful implantation. Formation of the decidua requires increased glucose metabolism via the pentose phosphate pathway and glycolysis. After decidualization, the cells switch to aerobic glycolysis to produce ATP. Paradoxically, the decidua also stores large amounts of glucose as glycogen. Too little glucose or an inability to take up glucose impairs embryo development and decidualization. Conversely, too much glucose inhibits these same processes. This likely contributes to the reduced pregnancy rates associated with conditions like obesity and diabetes. Collectively, precise control of glucose metabolism is important for several endometrial processes required to establish a successful pregnancy. The factors regulating these metabolic processes remain poorly understood.
PubMed: 37934727
DOI: 10.1530/RAF-23-0016 -
Pathogens (Basel, Switzerland) Dec 2023Infection by species in pregnant animals and humans is associated with an increased risk of abortion, preterm birth, and transmission of the infection to the offspring.... (Review)
Review
Infection by species in pregnant animals and humans is associated with an increased risk of abortion, preterm birth, and transmission of the infection to the offspring. The pathogen has a marked tropism for the placenta and the pregnant uterus and has the ability to invade and replicate within cells of the maternal-fetal unit, including trophoblasts and decidual cells. Placentitis is a common finding in infected pregnant animals. Several proinflammatory factors have been found to be increased in both the placenta of -infected animals and in trophoblasts or decidual cells infected in vitro. As normal pregnancies require an anti-inflammatory placental environment during most of the gestational period, -induced placentitis is thought to be associated with the obstetric complications of brucellosis. A few studies suggest that the blockade of proinflammatory factors may prevent abortion in these cases.
PubMed: 38133333
DOI: 10.3390/pathogens12121450 -
Reproductive Biology and Endocrinology... Jul 2023Throughout the course of pregnancy, small maternal spiral arteries that are in contact with fetal tissue undergo structural remodeling, lose smooth muscle cells, and... (Review)
Review
BACKGROUND
Throughout the course of pregnancy, small maternal spiral arteries that are in contact with fetal tissue undergo structural remodeling, lose smooth muscle cells, and become less responsive to vasoconstrictors. Additionally, placental extravillous trophoblasts invade the maternal decidua to establish an interaction between the fetal placental villi with the maternal blood supply. When successful, this process enables the transport of oxygen, nutrients, and signaling molecules but an insufficiency leads to placental ischemia. In response, the placenta releases vasoactive factors that enter the maternal circulation and promote maternal cardiorenal dysfunction, a hallmark of preeclampsia (PE), the leading cause of maternal and fetal death. An underexplored mechanism in the development of PE is the impact of membrane-initiated estrogen signaling via the G protein-coupled estrogen receptor (GPER). Recent evidence indicates that GPER activation is associated with normal trophoblast invasion, placental angiogenesis/hypoxia, and regulation of uteroplacental vasodilation, and these mechanisms could explain part of the estrogen-induced control of uterine remodeling and placental development in pregnancy.
CONCLUSION
Although the relevance of GPER in PE remains speculative, this review provides a summary of our current understanding on how GPER stimulation regulates some of the features of normal pregnancy and a potential link between its signaling network and uteroplacental dysfunction in PE. Synthesis of this information will facilitate the development of innovative treatment options.
Topics: Female; Humans; Pregnancy; Estrogens; Placenta; Pre-Eclampsia; Receptors, Estrogen; Receptors, G-Protein-Coupled
PubMed: 37393260
DOI: 10.1186/s12958-023-01112-7 -
Reproductive Sciences (Thousand Oaks,... Nov 2023Recurrent spontaneous abortion (RSA) is one of the most common complications during pregnancy and seriously affects women's physical and mental health. About 50% of RSA...
Recurrent spontaneous abortion (RSA) is one of the most common complications during pregnancy and seriously affects women's physical and mental health. About 50% of RSA cases are of unknown etiology. Our previous study found that the decidual tissue of patients with unexplained recurrent spontaneous abortion (URSA) had low expression levels of serum and glucocorticoid-induced protein kinase (SGK) 1. Endometrial decidualization is a key link in the early stage of pregnancy and is crucial to the development and maintenance of pregnancy. Decidualization is the proliferation and differentiation of endometrial stromal cells into deciduals, which involves a complex physiological process such as ovarian steroid hormones (estrogen, progesterone, prolactin, etc.), growth factors, and intercellular signaling. The binding of estrogen and its receptor stimulates the synthesis of endometrial deciduating markers prolactin (PRL) and insulin-like growth factor binding protein 1 (IGFBP-1), which mediates the occurrence of decidualization. Among them, SGK1/ENaC is a signaling pathway closely related to decidualization. The purpose of this study was to further investigate the expression of SGK1 and decidualization-related molecules in the decidual tissue of URSA patients and to explore the potential mechanism of SGK1's protective effect in URSA patients and in mouse models. Decidual tissue samples from 30 URSA patients and 30 women who actively terminated pregnancy were collected, and a URSA mouse model was established and treated with dydrogesterone. Expression levels of SGK1 and its signaling pathway-related proteins (p-Nedd4-2, 14-3-3 protein and ENaC-a), estrogen and progesterone receptors (ERβ, PR), and decidualization markers (PRLR, IGFBP-1) were assessed. Our study found that SGK1, p-Nedd4-2, 14-3-3 proteins, and ENaC-a expression levels were reduced in the decidual tissue, the SGK1/ENaC signaling pathway was inhibited, and the expression levels of the decidualization markers PRLR and IGFBP-1 were downregulated in the URSA group compared with the controls. Additionally, the concentrations of E, P, and PRL in the serum of mice were decreased in the URSA group compared with the controls. However, SGK1/ENaC pathway-related proteins, estrogen and progesterone and their receptors, and decidualization-related molecules were upregulated by dydrogesterone. These data suggest that estrogen and progesterone can induce decidualization by activating the SGK1/ENaC signaling pathway; disruption of this pathway can lead to the development of URSA. Dydrogesterone can increase the expression level of SGK1 protein in decidual tissue.
Topics: Humans; Pregnancy; Female; Mice; Animals; Progesterone; Decidua; Insulin-Like Growth Factor Binding Protein 1; Abortion, Spontaneous; Prolactin; Dydrogesterone; Signal Transduction; Estrogens; Abortion, Habitual; Stromal Cells
PubMed: 37280474
DOI: 10.1007/s43032-023-01273-1 -
The Journal of Maternal-fetal &... Dec 2023Unexplained recurrent pregnancy loss has been a a challenging research task to experts since there is no explicit pathophysiological mechanism and therefore, the...
BACKGROUND AND AIM
Unexplained recurrent pregnancy loss has been a a challenging research task to experts since there is no explicit pathophysiological mechanism and therefore, the treatment remains elusive. Immunological imbalance and morphological abnormalities are under investigation. This study aims to evaluate the implication of MMP-2, MMP-9, EGFR, and IL-8 in recurrent pregnancy loss cases.
MATERIALS & METHODS
The study was carried out through comparison among two groups; the unexplained miscarriage group which consisted of 22 women, and the control group consisted of 18 women, who had electively terminated their pregnancies. Both groups were in the first trimester of gestation. The specimens included the trophoblast, decidua basalis, and decidua parietalis. The study was conducted immunohistochemical methods. Antibodies were used against MMP-2, MMP-9, EGFR, and IL-8. The results were presented at a contingency table and were statistically analyzed with the Chi-Square Test (X).
RESULTS
There were remarkable disparities in some cases in the comparison of the two groups. MMP-9 was detected significantly high in recurrent pregnancy loss (RPL) cases, both on trophoblastic and decidual specimens (-value < .00001), MMP-2 displayed no difference among the two groups (mild to moderate detection on trophoblast and almost negative on decidual tissues). EGFR was highly detected in trophoblastic tissue (-value = .014). IL-8 detection was particularly different in both trophoblast and decidua parietalis of the two groups (-value < .01).
CONCLUSION
The study revealed both morphological and immunological dysregulations that might participate in the RPL pathogenesis.
Topics: Female; Humans; Pregnancy; Abortion, Habitual; Decidua; ErbB Receptors; Interleukin-8; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Pregnancy Trimester, First; Trophoblasts
PubMed: 37258409
DOI: 10.1080/14767058.2023.2218523 -
JCI Insight Sep 2023Maternal decidual CD8+ T cells must integrate the antithetical demands of providing immunity to infection while maintaining immune tolerance for fetal and placental...
Maternal decidual CD8+ T cells must integrate the antithetical demands of providing immunity to infection while maintaining immune tolerance for fetal and placental antigens. Human decidual CD8+ T cells were shown to be highly differentiated memory T cells with mixed signatures of dysfunction, activation, and effector function. However, no information is present on how specificity for microbial or fetal antigens relates to their function or dysfunction. In addition, a key question, whether decidual CD8+ T cells include unique tissue-resident memory T cells (Trm) or also effector memory T cell (Tem) types shared with peripheral blood populations, is unknown. Here, high-dimensional flow cytometry of decidual and blood CD8+ T cells identified 2 Tem populations shared in blood and decidua and 9 functionally distinct Trm clusters uniquely found in decidua. Interestingly, fetus- and virus-specific decidual CD8+ Trm cells had similar features of inhibition and cytotoxicity, with no significant differences in their expression of activation, inhibitory, and cytotoxic molecules, suggesting that not all fetus-specific CD8+ T cell responses are suppressed at the maternal-fetal interface. Understanding how decidual CD8+ T cell specificity relates to their function and tissue residency is crucial in advancing understanding of their contribution to placental inflammation and control of congenital infections.
Topics: Pregnancy; Humans; Female; Placenta; CD8-Positive T-Lymphocytes; Immune Tolerance; Cell Differentiation; Fetus
PubMed: 37681414
DOI: 10.1172/jci.insight.171806 -
Frontiers in Immunology 2023Term birth (TB) and preterm birth (PTB) are characterized by uterine contractions, rupture of the chorioamniotic membrane, decidual activation, and other physiological...
BACKGROUND
Term birth (TB) and preterm birth (PTB) are characterized by uterine contractions, rupture of the chorioamniotic membrane, decidual activation, and other physiological and pathological changes. In this study, we hypothesize that inflammation can cause changes in mRNA expression and metabolic stability in the placenta, decidua, chorioamniotic membrane, uterus and peripheral blood, ultimately leading to PTB.
METHODS
To comprehensively assess the effects of inflammation on mRNA expression and metabolite production in different tissues of pregnancy, we used a mouse PTB model by intraperitoneally injecting lipopolysaccharide (LPS) and integrated transcriptomics and metabolomics studies.
RESULTS
Our analysis identified 152 common differentially expressed genes (DEGs) and 8 common differentially expressed metabolites (DEMs) in the placenta, decidua, chorioamniotic membrane, uterus, and peripheral blood, or placenta and uterus after LPS injection, respectively. Our bioinformatics analysis revealed significant enrichment of the NOD-like receptor signaling pathway (mmu04621), TNF signaling pathway (mmu04668), IL-17 signaling pathway (mmu04657), and NF-kappa B signaling pathway in the transcriptomics of different tissues, and Hormone synthesis, Lysosome, NOD-like receptor signaling pathway, and Protein digest and absorption pathway in metabolomics. Moreover, we found that several upstream regulators and master regulators, including STAT1, STAT3, and NFKB1, were altered after exposure to inflammation in the different tissues. Interaction network analysis of transcriptomics and metabolomics DEGs and DEMs also revealed functional changes in mice intraperitoneally injected with LPS.
CONCLUSIONS
Overall, our study identified significant and biologically relevant alterations in the placenta, decidua, chorioamniotic membrane, uterus, peripheral blood transcriptome and the placenta and uterus metabolome in mice exposed to LPS. Thus, a comprehensive analysis of different pregnancy tissues in mice intraperitoneally injected with LPS by combining transcriptomics and metabolomics may help to systematically understand the local and systemic changes associated with PTB caused by inflammation.
Topics: Infant, Newborn; Female; Pregnancy; Humans; Animals; Mice; Lipopolysaccharides; Transcriptome; Premature Birth; Metabolomics; Disease Models, Animal; Inflammation; NLR Proteins; RNA, Messenger
PubMed: 37649476
DOI: 10.3389/fimmu.2023.1213902 -
Nature Communications Feb 2024During human pregnancy, extravillous trophoblasts play crucial roles in placental invasion into the maternal decidua and spiral artery remodeling. However, regulatory...
During human pregnancy, extravillous trophoblasts play crucial roles in placental invasion into the maternal decidua and spiral artery remodeling. However, regulatory factors and their action mechanisms modulating human extravillous trophoblast specification have been unknown. By analyzing dynamic changes in transcriptome and enhancer profile during human trophoblast stem cell to extravillous trophoblast differentiation, we define stage-specific regulators, including an early-stage transcription factor, TFAP2C, and multiple late-stage transcription factors. Loss-of-function studies confirm the requirement of all transcription factors identified for adequate differentiation, and we reveal that the dynamic changes in the levels of TFAP2C are essential. Notably, TFAP2C pre-occupies the regulatory elements of the inactive extravillous trophoblast-active genes during the early stage of differentiation, and the late-stage transcription factors directly activate extravillous trophoblast-active genes, including themselves as differentiation further progresses, suggesting sequential actions of transcription factors assuring differentiation. Our results reveal stage-specific transcription factors and their inter-connected regulatory mechanisms modulating extravillous trophoblast differentiation, providing a framework for understanding early human placentation and placenta-related complications.
Topics: Pregnancy; Humans; Female; Placenta; Extravillous Trophoblasts; Trophoblasts; Cell Differentiation; Transcription Factors; Stem Cells
PubMed: 38346993
DOI: 10.1038/s41467-024-45669-2 -
Clinical and Translational Medicine Feb 2024Defective decidualization of endometrial stromal cells (ESCs) in endometriosis (EM) patients leads to inadequate endometrial receptivity and EM-associated infertility....
Defective decidualization of endometrial stromal cells (ESCs) in endometriosis (EM) patients leads to inadequate endometrial receptivity and EM-associated infertility. Hypoxia is an inevitable pathological process of EM and participates in deficient decidualization of the eutopic secretory endometrium. Enhancer of zeste homology 2 (EZH2) is a methyltransferase which catalyses H3K27Me3, leading to decreased expression levels of target genes. Although EZH2 expression is low under normal decidualization, it is abundantly increased in the eutopic secretory endometrium of EM and is induced by hypoxia. Chromatin immunoprecipitation-PCR results revealed that decidua marker IGFBP1 is a direct target of EZH2, partially explaining the increased levels of histone methylation modification in defected decidualization of EM. To mechanism controlling this, we examined the effects of hypoxia on EZH2 and decidualization. EZH2 mRNA showed decreased m A modification and increased expression levels under hypoxia and decidualization combined treatment. Increased EZH2 expression was due to the increased expression of m A demethylase ALKBH5 and decreased expression of the m A reader protein YTHDF2. YTHDF2 directly bind to the m A modification site of EZH2 to promote EZH2 mRNA degradation in ESCs. Moreover, selective Ezh2 depletion in mouse ESCs increased endometrial receptivity and improved mouse fertility by up-regulating decidua marker IGFBP1 expression. This is the first report showing that YTHDF2 can act as a m A reader to promote decidualization by decreasing the stability of EZH2 mRNA and further increasing the expression of IGFBP1 in ESCs. Taken together, our findings highlight the critical role of EZH2/H3K27Me3 in decidualization and reveal a novel epigenetic mechanism by which hypoxia can suppress EM decidualization by decreasing the m A modification of EZH2 mRNA.
Topics: Female; Humans; Animals; Mice; Endometriosis; Histones; RNA; Infertility; Transcription Factors; RNA, Messenger; Methylation; Hypoxia
PubMed: 38344897
DOI: 10.1002/ctm2.1564