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International Journal of Molecular... Mar 2020Reproduction is a fundamental process for the preservation of the human species. This process requires a sequence of orchestrated events that are necessary for a... (Review)
Review
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.
Topics: Abortion, Habitual; Animals; Decidua; Embryo Implantation; Female; Humans; MicroRNAs; Pregnancy; Primates
PubMed: 32183093
DOI: 10.3390/ijms21061973 -
Frontiers in Immunology 2021Recurrent pregnancy loss (RPL) is a common fertility problem that affects 1%-2% of couples all over the world. Despite exciting discoveries regarding the important roles...
Recurrent pregnancy loss (RPL) is a common fertility problem that affects 1%-2% of couples all over the world. Despite exciting discoveries regarding the important roles of the decidual natural killer cell (dNK) and regulatory T cell in pregnancy, the immune heterogeneity in patients with unexplained recurrent pregnancy loss (URPL) remains elusive. Here, we profiled the transcriptomes of 13,953 CD45 cells from three normal and three URPL deciduas. Based on our data, the cellular composition revealed three major populations of immune cells including dNK cell, T cell, and macrophage, and four minor populations including monocytes, dendritic cell (DC), mast cell, and B cell. Especially, we identified a subpopulation of CSF1+ CD59+ KIRs-expressing dNK cells in normal deciduas, while the proportion of this subpopulation was decreased in URPL deciduas. We also identified a small subpopulation of activated dDCs that were accumulated mainly in URPL deciduas. Furthermore, our data revealed that in decidua at early pregnancy, CD8 T cells exhibited cytotoxic properties. The decidual macrophages expressed high levels of both M1 and M2 feature genes, which made them unique to the conventional M1/M2 classification. Our single-cell data revealed the immune heterogeneity in decidua and the potentially pathogenic immune variations in URPL.
Topics: Abortion, Habitual; CD8-Positive T-Lymphocytes; Decidua; Dendritic Cells; Female; Humans; Killer Cells, Natural; Macrophages; RNA-Seq
PubMed: 34168655
DOI: 10.3389/fimmu.2021.689019 -
Frontiers in Immunology 2021Pregnancy is a unique type of immunological process. Healthy pregnancy is associated with a series of inflammatory events: implantation (inflammation), gestation... (Review)
Review
Pregnancy is a unique type of immunological process. Healthy pregnancy is associated with a series of inflammatory events: implantation (inflammation), gestation (anti-inflammation), and parturition (inflammation). As the most abundant leukocytes during pregnancy, natural killer (NK) cells are recruited and activated by ovarian hormones and have pivotal roles throughout pregnancy. During the first trimester, NK cells represent up to 50-70% of decidua lymphocytes. Differently from peripheral-blood NK cells, decidual natural killer (dNK) cells are poorly cytolytic, and they release cytokines/chemokines that induce trophoblast invasion, tissue remodeling, embryonic development, and placentation. NK cells can also shift to a cytotoxic identity and carry out immune defense if infected by pathogens. At late gestation, premature activation of NK cells can lead to a breakdown of tolerance of the maternal-fetal interface and, subsequently, can result in preterm birth. This review is focused on the role of dNK cells in normal pregnancy and pathological pregnancy, including preeclampsia, recurrent spontaneous abortion, endometriosis, and recurrent implantation failure. dNK cells could be targets for the treatment of pregnancy complications.
Topics: Animals; Cytokines; Cytotoxicity, Immunologic; Decidua; Embryo Implantation; Female; Fetal Development; Histocompatibility, Maternal-Fetal; Humans; Immune Tolerance; Killer Cells, Natural; Parturition; Phenotype; Placentation; Pregnancy; Pregnancy Complications; Signal Transduction
PubMed: 34512661
DOI: 10.3389/fimmu.2021.728291 -
Frontiers in Immunology 2019A successful pregnancy requires a fine-tuned and highly regulated balance between immune activation and embryonic antigen tolerance. Since the fetus is semi-allogeneic,... (Review)
Review
A successful pregnancy requires a fine-tuned and highly regulated balance between immune activation and embryonic antigen tolerance. Since the fetus is semi-allogeneic, the maternal immune system should exert tolerant to the fetus while maintaining the defense against infection. The maternal-fetal interface consists of different immune cells, such as decidual natural killer (dNK) cells, macrophages, T cells, dendritic cells, B cells, and NKT cells. The interaction between immune cells, decidual stromal cells, and trophoblasts constitute a vast network of cellular connections. A cellular immunological imbalance may lead to adverse pregnancy outcomes, such as recurrent spontaneous abortion, pre-eclampsia, pre-term birth, intrauterine growth restriction, and infection. Dynamic changes in immune cells at the maternal-fetal interface have not been clearly stated. While many studies have described changes in the proportions of immune cells in the normal maternal-fetus interface during early pregnancy, few studies have assessed the immune cell changes in mid and late pregnancy. Research on pathological pregnancy has provided clues about these dynamic changes, but a deeper understanding of these changes is necessary. This review summarizes information from previous studies, which may lay the foundation for the diagnosis of pathological pregnancy and put forward new ideas for future studies.
Topics: Decidua; Female; Humans; Immunity, Maternally-Acquired; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Trophoblasts
PubMed: 31681264
DOI: 10.3389/fimmu.2019.02317 -
Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids.ELife Sep 2021Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust...
Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterized endometrial assembloids, consisting of gland-like organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by eliminating the emergence of senescent decidual cells. In co-culture experiments, accelerated decidualization resulted in entrapment of collapsed human blastocysts in a robust, static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Our findings suggest that decidual senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.
Topics: Cellular Senescence; Coculture Techniques; Decidua; Embryo Implantation; Endometrium; Female; Humans; Organoids; Pregnancy; Stromal Cells
PubMed: 34487490
DOI: 10.7554/eLife.69603 -
Frontiers in Immunology 2021Recurrent spontaneous abortion (RSA) is a common complication of pregnancy that affects the physical and mental health of pregnant women, and approximately 50% of the...
Recurrent spontaneous abortion (RSA) is a common complication of pregnancy that affects the physical and mental health of pregnant women, and approximately 50% of the mechanisms are unclear. Our previous studies have found that high mobility group box 1 (HMGB1) molecules are highly expressed at the maternal-fetal interface of unexplained recurrent spontaneous abortion (URSA) patients. The purpose of this study was to further detect the expression of HMGB1 and pyroptosis in decidual tissue of URSA patients, and explore the potential mechanism of the protective role of HMGB1 in URSA patients and mouse model. The decidua tissues of 75 URSA patients and 75 women who actively terminated pregnancy were collected, and URSA mouse models were established and treated with HMGB1 inhibitor-aspirin. The expression of HMGB1, and their receptors (RAGE, TLR2, TLR4), pyroptosis-associated proteins (NLRP-3, caspase-1, GSDMD) and NF-κB was examined at the maternal-fetal interface of human and mouse. Our study found that HMGB1, NLRP-3, Caspase-1, GSDMD, RAGE, TLR2 and TLR4 were highly expressed and NF-κB signaling pathway were activated in the decidua tissue of URSA group. Moreover, immune cell disorder and co-localization of HMGB1 and macrophages were found at the maternal-fetal interface of URSA mice. However, HMGB1, TLR2, TLR4, NF-κB, and pyroptosis-associated proteins can be down-regulated by administering low-dose aspirin. These data may indicate that highly expressed HMGB1 was actively secreted by macrophages and then activated pyroptosis through the TLR2/TLR4-NF-κB pathway to cause aseptic inflammation, leading to the occurrence and development of URSA. Moreover, low-dose aspirin can reduce HMGB1 protein levels of serum and decidual in URSA.
Topics: Abortion, Habitual; Adult; Animals; Aspirin; Biomarkers; Decidua; Disease Management; Disease Models, Animal; Disease Susceptibility; Female; Gene Expression; HMGB1 Protein; Humans; Immunohistochemistry; Macrophages; Mice; Models, Biological; NF-kappa B; Placenta; Pregnancy; Pyroptosis; Signal Transduction
PubMed: 35003098
DOI: 10.3389/fimmu.2021.782792 -
Frontiers in Immunology 2023Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality. Although increasing lines of evidence suggest that both the placenta and the decidua...
Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality. Although increasing lines of evidence suggest that both the placenta and the decidua likely play roles in the pathogenesis of PE, the molecular mechanism of PE remains elusive partly because of the heterogeneity nature of the maternal-fetal interface. In this study, we perform single-cell RNA-seq on the placenta and the decidual from patients with late-onset PE (LOPE) and women in normal pregnancy. Analyses of single-cell transcriptomes reveal that in LOPE, there are likely a global development deficiency of trophoblasts with impaired invasion of extravillous trophoblasts (EVT) and increased maternal immune rejection and inflammation in the placenta, while there are likely insufficient decidualization of decidual stromal cells (DSC), increased inflammation, and suppressed regulatory functions of decidual immune cells. These findings improve our understanding of the molecular mechanisms of PE.
Topics: Pregnancy; Humans; Female; Placentation; Pre-Eclampsia; Single-Cell Gene Expression Analysis; Decidua; Inflammation
PubMed: 37283740
DOI: 10.3389/fimmu.2023.1142273 -
Proceedings of the National Academy of... Sep 2022In humans, the uterus undergoes a dramatic transformation to form an endometrial stroma-derived secretory tissue, termed decidua, during early pregnancy. The decidua...
In humans, the uterus undergoes a dramatic transformation to form an endometrial stroma-derived secretory tissue, termed decidua, during early pregnancy. The decidua secretes various factors that act in an autocrine/paracrine manner to promote stromal differentiation, facilitate maternal angiogenesis, and influence trophoblast differentiation and development, which are critical for the formation of a functional placenta. Here, we investigated the mechanisms by which decidual cells communicate with each other and with other cell types within the uterine milieu. We discovered that primary human endometrial stromal cells (HESCs) secrete extracellular vesicles (EVs) during decidualization and that this process is controlled by a conserved HIF2α-RAB27B pathway. Mass spectrometry revealed that the decidual EVs harbor a variety of protein cargo, including cell signaling molecules, growth modulators, metabolic regulators, and factors controlling endothelial cell expansion and remodeling. We tested the hypothesis that EVs secreted by the decidual cells mediate functional communications between various cell types within the uterus. We demonstrated that the internalization of EVs, specifically those carrying the glucose transporter 1 (GLUT1), promotes glucose uptake in recipient HESCs, supporting and advancing the decidualization program. Additionally, delivery of HESC-derived EVs into human endothelial cells stimulated their proliferation and led to enhanced vascular network formation. Strikingly, stromal EVs also promoted the differentiation of trophoblast stem cells into the extravillous trophoblast lineage. Collectively, these findings provide a deeper understanding of the pleiotropic roles played by EVs secreted by the decidual cells to ensure coordination of endometrial differentiation and angiogenesis with trophoblast function during the progressive phases of decidualization and placentation.
Topics: Cell Differentiation; Decidua; Endothelial Cells; Extracellular Vesicles; Female; Humans; Neovascularization, Physiologic; Pregnancy; Stromal Cells; Trophoblasts
PubMed: 36095212
DOI: 10.1073/pnas.2200252119 -
ELife Jul 2023Decidualization is a process in which endometrial stromal fibroblasts differentiate into specialized secretory decidual cells and essential for the successful...
Decidualization is a process in which endometrial stromal fibroblasts differentiate into specialized secretory decidual cells and essential for the successful establishment of pregnancy. The underlying mechanism during decidualization still remains poorly defined. Because decidualization and fibroblast activation share similar characteristics, this study was to examine whether fibroblast activation is involved in decidualization. In our study, fibroblast activation-related markers are obviously detected in pregnant decidua and under in vitro decidualization. ACTIVIN A secreted under fibroblast activation promotes in vitro decidualization. We showed that arachidonic acid released from uterine luminal epithelium can induce fibroblast activation and decidualization through PGI and its nuclear receptor PPARδ. Based on the significant difference of fibroblast activation-related markers between pregnant and pseudopregnant mice, we found that embryo-derived TNF promotes CPLA phosphorylation and arachidonic acid release from luminal epithelium. Fibroblast activation is also detected under human in vitro decidualization. Similar arachidonic acid-PGI-PPARδ-ACTIVIN A pathway is conserved in human endometrium. Collectively, our data indicate that embryo-derived TNF promotes CPLA phosphorylation and arachidonic acid release from luminal epithelium to induce fibroblast activation and decidualization.
Topics: Pregnancy; Female; Humans; Animals; Mice; Decidua; PPAR delta; Arachidonic Acid; Endometrium; Fibroblasts; Stromal Cells
PubMed: 37458359
DOI: 10.7554/eLife.82970 -
Frontiers in Immunology 2023One pivotal aspect of early pregnancy is decidualization. The decidualization process includes two components: the differentiation of endometrial stromal cells to... (Review)
Review
One pivotal aspect of early pregnancy is decidualization. The decidualization process includes two components: the differentiation of endometrial stromal cells to decidual stromal cells (DSCs), as well as the recruitment and education of decidual immune cells (DICs). At the maternal-fetal interface, stromal cells undergo morphological and phenotypic changes and interact with trophoblasts and DICs to provide an appropriate decidual bed and tolerogenic immune environment to maintain the survival of the semi-allogeneic fetus without causing immunological rejection. Despite classic endocrine mechanism by 17 β-estradiol and progesterone, metabolic regulations do take part in this process according to recent studies. And based on our previous research in maternal-fetal crosstalk, in this review, we elaborate mechanisms of decidualization, with a special focus on DSC profiles from aspects of metabolism and maternal-fetal tolerance to provide some new insights into endometrial decidualization in early pregnancy.
Topics: Pregnancy; Female; Humans; Decidua; Endometrium; Estradiol; Fetus; Energy Metabolism
PubMed: 37404833
DOI: 10.3389/fimmu.2023.1203719