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Molecular and Cellular Endocrinology Jul 2012During the early stages of pregnancy, fertilized embryos must attach to the uterine epithelium, invade into the underlying uterine stroma, and the stroma must then... (Review)
Review
During the early stages of pregnancy, fertilized embryos must attach to the uterine epithelium, invade into the underlying uterine stroma, and the stroma must then differentiate in a process termed decidualization in order for a successful pregnancy to be initiated. The steroid hormone progesterone (P4) is an integral mediator of these early pregnancy events, exerting its effects via the progesterone receptor (PR). Insights gained from the use of mouse models and genomic profiling has identified many of the key molecules enlisted by PR to execute the paradigm of early pregnancy. This review describes several of the molecules through which the PR exerts its pleiotropic effects including ligands, receptors, chaperones, signaling proteins and transcription factors. Understanding these molecules and their concatenation is of vital importance to our ability to clinically treat reproductive health problems like infertility and endometriosis.
Topics: Animals; Decidua; Embryo Implantation; Female; Humans; Models, Biological; Receptors, Progesterone; Signal Transduction
PubMed: 21821095
DOI: 10.1016/j.mce.2011.07.027 -
Journal of Reproductive Immunology Aug 1998Insulin-like growth factors, IGF-I, IGF-II, and IGF binding protein (IGFBP-1) appear to play major roles in endometrial development during the menstrual cycle and in the... (Review)
Review
Insulin-like growth factors, IGF-I, IGF-II, and IGF binding protein (IGFBP-1) appear to play major roles in endometrial development during the menstrual cycle and in the process of implantation. The mitogenic, differentiative, and anti-apoptotic properties of these growth factors, as well as their spatial and temporal expression in cycling endometrium, suggest that they may participate in endometrial growth, differentiation, inhibition of apoptosis, and perhaps angiogenesis. IGFBP-1 is a major protein product of non-pregnant endometrium during the mid-late secretory phase and occurs in abundance in decidua. Its roles as an IGF-binding protein and as a trophoblast integrin ligand suggest that it may have multiple roles in endometrial development and in interactions between the decidua and the invading trophoblast. Precise elucidation of the mechanisms underlying IGF and IGFBP-1 action at the decidual-trophoblast interface in early pregnancy awaits further investigation. The future also awaits elucidation of the potential predictive utility of IGFBP-1 in serum and in decidua in, for example, pre-eclampsia and perhaps implantation failure.
Topics: Animals; Decidua; Embryo Implantation; Endometrium; Female; Humans; Insulin-Like Growth Factor Binding Protein 1; Pregnancy; Somatomedins; Trophoblasts
PubMed: 9786458
DOI: 10.1016/s0165-0378(98)00018-7 -
The Journal of Clinical Investigation Feb 2021Group A Streptococcus (GAS), a Gram-positive human-specific pathogen, yields 517,000 deaths annually worldwide, including 163,000 due to invasive infections and among...
Group A Streptococcus (GAS), a Gram-positive human-specific pathogen, yields 517,000 deaths annually worldwide, including 163,000 due to invasive infections and among them puerperal fever. Before efficient prophylactic measures were introduced, the mortality rate for mothers during childbirth was approximately 10%; puerperal fever still accounts for over 75,000 maternal deaths annually. Yet, little is known regarding the factors and mechanisms of GAS invasion and establishment in postpartum infection. We characterized the early steps of infection in an ex vivo infection model of the human decidua, the puerperal fever portal of entry. Coordinate analysis of GAS behavior and the immune response led us to demonstrate that (a) GAS growth was stimulated by tissue products; (b) GAS invaded tissue and killed approximately 50% of host cells within 2 hours, and these processes required SpeB protease and streptolysin O (SLO) activities, respectively; and (c) GAS impaired the tissue immune response. Immune impairment occurred both at the RNA level, with only partial induction of the innate immune response, and protein level, in an SLO- and SpeB-dependent manner. Our study indicates that efficient GAS invasion of the decidua and the restricted host immune response favored its propensity to develop rapid invasive infections in a gynecological-obstetrical context.
Topics: A549 Cells; Decidua; Endometriosis; Female; HeLa Cells; Humans; Streptococcal Infections; Streptococcus pyogenes
PubMed: 33320843
DOI: 10.1172/JCI130746 -
Molecular and Cellular Endocrinology Jun 2012Many women are affected by infertility and reproductive-associated disease such as endometriosis or endometrial cancer. Successful pregnancy is dependent on a healthy... (Review)
Review
Many women are affected by infertility and reproductive-associated disease such as endometriosis or endometrial cancer. Successful pregnancy is dependent on a healthy uterus that is fit to receive and support a fertilized embryo. The uterus is an endocrine organ, responsive to the presence of the ovarian steroid hormones, estrogen and progesterone, which activate transcription of target genes through the binding of their cognate receptors, the estrogen receptor and the progesterone receptor. Progesterone signaling has been demonstrated to be critical for the initiation and continuance of pregnancy. Through the induction of Ihh, Wnt, and Bmp pathways within the epithelial and stromal compartments of the uterus, embryo attachment and implantation occur followed by decidualization of the surrounding stroma. Furthermore, these pathways have been shown to be involved in uterine glandular development. This review highlights the integral role of uterine progesterone-mediated paracrine signaling in gland development and pregnancy.
Topics: Animals; Decidua; Embryo Implantation; Female; Humans; Paracrine Communication; Pregnancy; Receptors, Progesterone; Signal Transduction; Uterus
PubMed: 22115959
DOI: 10.1016/j.mce.2011.10.028 -
Frontiers in Immunology 2024Prior to pregnancy, hormonal changes lead to cellular adaptations in the endometrium allowing for embryo implantation. Critical for successful pregnancy establishment,...
INTRODUCTION
Prior to pregnancy, hormonal changes lead to cellular adaptations in the endometrium allowing for embryo implantation. Critical for successful pregnancy establishment, innate immune cells constitute a significant proportion of uterine cells prior to arrival of the embryo and throughout the first trimester in humans and animal models. Abnormal uterine immune cell function during implantation is believed to play a role in multiple adverse pregnancy outcomes. Current work in humans has focused on uterine immune cells present after pregnancy establishment, and limited in vitro models exist to explore unique functions of these cells.
METHODS
With single-cell RNA-sequencing (scRNAseq), we comprehensively compared the human uterine immune landscape of the endometrium during the window of implantation and the decidua during the first trimester of pregnancy.
RESULTS
We uncovered global and cell-type-specific gene signatures for each timepoint. Immune cells in the endometrium prior to implantation expressed genes associated with immune metabolism, division, and activation. In contrast, we observed widespread interferon signaling during the first trimester of pregnancy. We also provide evidence of specific inflammatory pathways enriched in pre- and post-implantation macrophages and natural killer (NK) cells in the uterine lining. Using our novel implantation-on-a-chip (IOC) to model human implantation ex vivo, we demonstrate for the first time that uterine macrophages strongly promote invasion of extravillous trophoblasts (EVTs), a process essential for pregnancy establishment. Pre- and post-implantation uterine macrophages promoted EVT invasion to a similar degree as pre- and post-implantation NK cells on the IOC.
CONCLUSIONS
This work provides a foundation for further investigation of the individual roles of uterine immune cell subtypes present prior to embryo implantation and during early pregnancy, which will be critical for our understanding of pregnancy complications associated with abnormal trophoblast invasion and placentation.
Topics: Pregnancy; Female; Animals; Humans; Decidua; Embryo Implantation; Uterus; Killer Cells, Natural; Macrophages
PubMed: 38566989
DOI: 10.3389/fimmu.2024.1364036 -
American Journal of Reproductive... Jun 2010It is widely accepted that pregnancy constitutes a unique developmental event. Unprecedented intrauterine actions of angiogenesis, immunity, and neuroendocrine... (Review)
Review
It is widely accepted that pregnancy constitutes a unique developmental event. Unprecedented intrauterine actions of angiogenesis, immunity, and neuroendocrine regulation are juxtaposed to mechanisms of senescence that enable fetal growth and protection. The suppressive and regulatory factors that facilitate healthy pregnancy are under investigation. In non-pregnant systems of infection and inflammation, the cytokine interleukin-10 (IL-10) has been widely investigated because of its potential as a key immunosuppressant in response to a multitude of inflammatory events. In the context of pregnancy, IL-10 levels increase markedly in women during early pregnancy and remain elevated well into the third trimester immediately prior to onset of labor. The role of IL-10 during pregnancy as a suppressor of active maternal immunity to allow acceptance of the fetal allograft has been a point of study. Moreover, secretion of IL-10 by a diverse set of maternal and fetal cells has proven to aid in the orchestration of normal processes of pregnancy. Interestingly, some of the more profound findings regarding the actions of IL-10 during pregnancy have manifested from research that focuses on aberrant pregnancy outcomes as a result of inflammation, hormonal imbalances, or gene-environment interactions. This review focuses on the role of IL-10 as a facilitator of successful pregnancy both as an immune suppressive agent and a mediator of cross talk between the placenta and the decidua. Importantly, we discuss investigations on adverse pregnancy conditions to further elucidate the multifarious role of IL-10 at the maternal-fetal interface.
Topics: Animals; Decidua; Female; Humans; Inflammation; Interleukin-10; Mice; Mice, Inbred CBA; Mice, Inbred DBA; Placenta; Pregnancy; Pregnancy Outcome
PubMed: 20163400
DOI: 10.1111/j.1600-0897.2010.00810.x -
Reproduction (Cambridge, England) Aug 2011Lipoxin A(4) is a lipid mediator that elicits anti-inflammatory and pro-resolution actions via its receptor, formyl peptide receptor 2 (FPR2/ALX). In this study, we...
Lipoxin A(4) is a lipid mediator that elicits anti-inflammatory and pro-resolution actions via its receptor, formyl peptide receptor 2 (FPR2/ALX). In this study, we aimed to investigate the expression and potential role of lipoxin A(4) and FPR2/ALX in the regulation of inflammation associated with cyclical remodeling of the human endometrium across the menstrual cycle and during early pregnancy. Using quantitative RT-PCR analysis, we found that FPR2/ALX expression is upregulated during the menstrual phase of the cycle and in decidua tissue from the first trimester of pregnancy. We localized the site of expression of FPR2/ALX in menstrual phase endometrium and first-trimester decidua tissue to glandular epithelial cells and cells within the stromal compartment, including cells lining the blood vessels and immune cells. Measurement of serum lipoxin A(4) by ELISA revealed no difference in its levels across the menstrual cycle but an elevation in early pregnancy (P<0.001). We found that lipoxin A(4) was regulated by human chorionic gonadotrophin (hCG) during early pregnancy, because treatment of human decidua tissue with hCG increased lipoxin A(4) release (P<0.01). Finally, we have shown that lipoxin A(4) can suppress phorbol myristate acetate-induced expression of the inflammatory cytokines interleukin 6 and 8 in human endometrium and decidua tissue. These results demonstrate for the first time that lipoxin A(4) and its receptor FPR2/ALX can regulate inflammatory events in the human endometrium and decidua of early pregnancy.
Topics: Adult; Chorionic Gonadotropin; Decidua; Endometrium; Epithelial Cells; Female; Gene Expression Regulation; Humans; Inflammation Mediators; Interleukins; Lipoxins; Menstrual Cycle; Pregnancy; Pregnancy Trimester, First; RNA, Messenger; Receptors, Formyl Peptide; Receptors, Lipoxin; Stromal Cells; Tetradecanoylphorbol Acetate; Tissue Culture Techniques; Young Adult
PubMed: 21555360
DOI: 10.1530/REP-11-0021 -
Cell Adhesion & Migration Mar 2016Chemokine network is central to the innate and adaptive immunity and entails a variety of proteins and membrane receptors that control physiological processes such as... (Review)
Review
Chemokine network is central to the innate and adaptive immunity and entails a variety of proteins and membrane receptors that control physiological processes such as wound healing, angiogenesis, embryo growth and development. During early pregnancy, the chemokine network coordinates not only the recruitment of different leukocyte populations to generate the maternal-placental interface, but also constitutes an additional checkpoint for tissue homeostasis maintenance. The normal switch from a pro-inflammatory to an anti-inflammatory predominant microenvironment characteristic of the post-implantation stage requires redundant immune tolerance circuits triggered by key master regulators. In this review we will focus on the recruitment and conditioning of maternal immune cells to the uterus at the early implantation period with special interest on high plasticity macrophages and dendritic cells and their ability to induce regulatory T cells. We will also point to putative immunomodulatory polypeptides involved in immune homeostasis maintenance at the maternal-placental interface.
Topics: Animals; Cell Movement; Chemokines; Decidua; Embryo Implantation; Female; Humans; Leukocytes; Pregnancy; Trophoblasts
PubMed: 26891097
DOI: 10.1080/19336918.2015.1135285 -
Frontiers in Endocrinology 2022Natural killer (NK) cells are the predominant maternal uterine immune cell component, and they densely populate uterine mucosa to promote key changes in the... (Review)
Review
Natural killer (NK) cells are the predominant maternal uterine immune cell component, and they densely populate uterine mucosa to promote key changes in the post-ovulatory endometrium and in early pregnancy. It is broadly accepted that (a) immature, inactive endometrial NK (eNK) cells in the pre-ovulatory endometrium become activated and transition into decidual NK (dNK) cells in the secretory stage, peri-implantation endometrium, and continue to mature into early pregnancy; and (b) that secretory-stage and early pregnancy dNK cells promote uterine vascular growth and mediate trophoblast invasion, but do not exert their killing function. However, this may be an overly simplistic view. Evidence of specific dNK functional killer roles, as well as opposing effects of dNK cells on the uterine vasculature before and after conception, indicates the presence of a transitory secretory-stage dNK cell (s-dNK) phenotype with a unique angiodevelopmental profile during the peri-implantation period, that is that is functionally distinct from the angiomodulatory dNK cells that promote vessel destabilisation and vascular cell apoptosis to facilitate uterine vascular changes in early pregnancy. It is possible that abnormal activation and differentiation into the proposed transitory s-dNK phenotype may have implications in uterine pathologies ranging from infertility to cancer, as well as downstream effects on dNK cell differentiation in early pregnancy. Further, dysregulated transition into the angiomodulatory dNK phenotype in early pregnancy will likely have potential repercussions for adverse pregnancy outcomes, since impaired dNK function is associated with several obstetric complications. A comprehensive understanding of the uterine NK cell temporal differentiation pathway may therefore have important translational potential due to likely NK phenotypic functional implications in a range of reproductive, obstetric, and gynaecological pathologies.
Topics: Cell Differentiation; Decidua; Female; Humans; Killer Cells, Natural; Pregnancy; Reproductive Health; Trophoblasts
PubMed: 35832424
DOI: 10.3389/fendo.2022.904744 -
Journal of Pregnancy 2016The human decidua is a specialized tissue characterized by embryo-receptive properties. It is formed during the secretory phase of menstrual cycle from uterine mucosa... (Review)
Review
The human decidua is a specialized tissue characterized by embryo-receptive properties. It is formed during the secretory phase of menstrual cycle from uterine mucosa termed endometrium. The decidua is composed of glands, immune cells, blood and lymph vessels, and decidual stromal cells (DSCs). In the process of decidualization, which is controlled by oestrogen and progesterone, DSCs acquire specific functions related to recognition, selection, and acceptance of the allogeneic embryo, as well as to development of maternal immune tolerance. In this review we discuss the relationship between the decidualization of DSCs and pathological obstetrical and gynaecological conditions. Moreover, the critical influence of DSCs on local immune cells populations as well as their relationship to the onset and maintenance of immune tolerance is described.
Topics: Decidua; Embryo Implantation; Endometrium; Estrogens; Female; Humans; Immune Tolerance; Pregnancy; Progesterone; Stromal Cells
PubMed: 27239344
DOI: 10.1155/2016/8689436