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International Journal of Biological... 2022In some cases of spontaneous miscarriage (SM), the exact etiology cannot be determined. Autophagy, which is responsible for cellular survival under stress conditions,... (Review)
Review
In some cases of spontaneous miscarriage (SM), the exact etiology cannot be determined. Autophagy, which is responsible for cellular survival under stress conditions, has also been implicated in many diseases. Recently, it is also surmised to be correlated with SM. However, the detailed mechanism remains elusive. In fact, there are several essential steps during pregnancy establishment and maintenance: trophoblasts invasion, placentation, decidualization, enrichment and infiltration of decidua immune cells (e.g., natural killer, macrophage and T cells). Accordingly, upstream molecules and downstream effects of autophagy are discussed in these processes, respectively. Of note, autophagy regulates the crosstalk between these cells at the maternal-fetal interface as well. Aberrant autophagy is found in villi, decidual stromal cells, peripheral blood mononuclear cells in SM patients, although the findings are inconsistent among different studies. Furthermore, potential treatments targeting autophagy are included, during which rapamycin and vitamin D are hot-spots in recent literatures. To conclude, a moderately activated autophagy is deeply involved in pregnancy, suggesting that autophagy should be a regulator and promising target for treating SM.
Topics: Abortion, Spontaneous; Autophagy; Decidua; Female; Humans; Leukocytes, Mononuclear; Pregnancy; Trophoblasts
PubMed: 35173545
DOI: 10.7150/ijbs.68335 -
Orvosi Hetilap Nov 2022An essential component of successful conception and pregnancy is decidualization, which involves structural and functional transformation of the endometrium. The process... (Review)
Review
An essential component of successful conception and pregnancy is decidualization, which involves structural and functional transformation of the endometrium. The process involves structural changes in the uterine mucosa, transformation of spiral arterioles, numerical and functional adaptation of leukocytes in the endometrium and their subsequent migration, and functional and morphological changes in decidual stromal cells. As part of decidualization, trophoblast cells of embryonic origin perform a physiological invasion of maternal tissue to create the placenta. The success of the process is due to the special antigenicity of the trophoblast cells and the immune communication between the graft (fetus) and the host (mother) through hormones, cytokines and multiple receptorligand connections. Disorders of these processes are the basis of several diseases that threaten conception, implantation, and successful pregnancy, such as recurrent miscarriage, preeclampsia, intrauterine retardation, or preterm birth. In this article, we review the anatomical, immunological, and molecular basis of physiological decidualization to address common disorders in the clinical practice of obstetrics that are related to a dysfunctional decidualization.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Decidua; Premature Birth; Embryo Implantation; Endometrium; Trophoblasts; Stromal Cells
PubMed: 36373581
DOI: 10.1556/650.2022.32626 -
Circulation May 2024Preeclampsia is a serious disease of pregnancy that lacks early diagnosis methods or effective treatment, except delivery. Dysregulated uterine immune cells and spiral...
BACKGROUND
Preeclampsia is a serious disease of pregnancy that lacks early diagnosis methods or effective treatment, except delivery. Dysregulated uterine immune cells and spiral arteries are implicated in preeclampsia, but the mechanistic link remains unclear.
METHODS
Single-cell RNA sequencing and spatial transcriptomics were used to identify immune cell subsets associated with preeclampsia. Cell-based studies and animal models including conditional knockout mice and a new preeclampsia mouse model induced by recombinant mouse galectin-9 were applied to validate the pathogenic role of a CD11c subpopulation of decidual macrophages (dMφ) and to determine its underlying regulatory mechanisms in preeclampsia. A retrospective preeclampsia cohort study was performed to determine the value of circulating galectin-9 in predicting preeclampsia.
RESULTS
We discovered a distinct CD11c dMφ subset that inhibits spiral artery remodeling in preeclampsia. The proinflammatory CD11c dMφ exhibits perivascular enrichment in the decidua from patients with preeclampsia. We also showed that trophoblast-derived galectin-9 activates CD11c dMφ by means of CD44 binding to suppress spiral artery remodeling. In 3 independent preeclampsia mouse models, placental and plasma galectin-9 levels were elevated. Galectin-9 administration in mice induces preeclampsia-like phenotypes with increased CD11c dMφ and defective spiral arteries, whereas galectin-9 blockade or macrophage-specific CD44 deletion prevents such phenotypes. In pregnant women, increased circulating galectin-9 levels in the first trimester and at 16 to 20 gestational weeks can predict subsequent preeclampsia onset.
CONCLUSIONS
These findings highlight a key role of a distinct perivascular inflammatory CD11c dMφ subpopulation in the pathogenesis of preeclampsia. CD11c dMφ activated by increased galectin-9 from trophoblasts suppresses uterine spiral artery remodeling, contributing to preeclampsia. Increased circulating galectin-9 may be a biomarker for preeclampsia prediction and intervention.
Topics: Pre-Eclampsia; Pregnancy; Female; Animals; Vascular Remodeling; Galectins; Macrophages; Mice; Humans; Decidua; Mice, Knockout; Uterus; Disease Models, Animal; Hyaluronan Receptors; Retrospective Studies; Mice, Inbred C57BL; CD11 Antigens
PubMed: 38314577
DOI: 10.1161/CIRCULATIONAHA.123.064391 -
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 -
Tissue & Cell Oct 2021Decidualization is characterized by a series of genetic, metabolic, morphological, biochemical, vascular and immune changes occurring in the endometrial stroma in... (Review)
Review
Decidualization is characterized by a series of genetic, metabolic, morphological, biochemical, vascular and immune changes occurring in the endometrial stroma in response to the implanting embryo or even before conception and involves the stromal cells of the endometrium. It is a fundamental reproductive event occurring in mammalian species with hemochorial placentation. A growing body of experimental and clinical evidence strongly suggests that defective or disrupted decidualization contributes to the establishment of an inappropriate maternal-fetal interface. This has relevant clinical consequences, ranging from recurrent implantation failure and recurrent pregnancy loss in early pregnancy to several significant complications of advanced gestation. Moreover, recent evidence indicates that selected diseases of the endometrium, such as chronic endometritis and endometriosis, can have a detrimental impact on the decidualization response in the endometrium and may help explain some aspects of the reduced reproductive outcome associated with these conditions. Further research efforts are needed to fully understand the biomolecular mechanisms ans events underlying an abnormal decidualization response. This will permit the development of new diagnostic and therapeutic strategies aimed to improve the likelihood of achieveing a successful pregnancy.
Topics: Animals; Biological Evolution; Decidua; Endometrium; Female; Humans; Pregnancy; Uterine Diseases
PubMed: 34217128
DOI: 10.1016/j.tice.2021.101586 -
Current Opinion in Immunology Feb 2022The human maternal-fetal interface is an immunologically complex environment that must balance the divergent demands of tolerance towards the developing fetus with... (Review)
Review
The human maternal-fetal interface is an immunologically complex environment that must balance the divergent demands of tolerance towards the developing fetus with anti-pathogen defense. The innate immune responses at the maternal-fetal interface that function in anti-microbial defense have been understudied to-date and how 'TORCH' pathogens evade maternal innate immunity to infect the fetus remains poorly understood. Herein, we discuss how newly described decidual innate lymphoid cells and maternal placenta-associated macrophage subsets may be involved in anti-pathogen defense. Moreover, we outline recent advances in our understanding of how placental trophoblasts and fetal-derived macrophages (Hofbauer cells) function in anti-microbial defense. In summary, we highlight current gaps in knowledge and describe novel experimental models of the human decidua and placenta that are poised to advance our knowledge of innate immune defenses at the maternal-fetal interface.
Topics: Decidua; Female; Humans; Immunity, Innate; Lymphocytes; Placenta; Pregnancy; Trophoblasts
PubMed: 34768027
DOI: 10.1016/j.coi.2021.10.007 -
American Journal of Obstetrics and... Feb 2022Preeclampsia is a major obstetrical complication with short- and long-term life-threatening consequences for both mother and child. Shallow cytotrophoblast invasion... (Review)
Review
Preeclampsia is a major obstetrical complication with short- and long-term life-threatening consequences for both mother and child. Shallow cytotrophoblast invasion through the uterine decidua into the spiral arteries is implicated in the pathogenesis of preeclampsia, although the cause of deficient arterial invasion remains unknown. Research that is focused on the "soil"-the maternal decidua-highlights the importance of this poorly understood but influential uterine layer. Decidualization of endometrial cells regulates embryo invasion, which is essential for spiral artery remodeling and establishing the maternal-fetal interface. Exploration of the association between impaired decidualization and preeclampsia revealed suboptimal endometrial maturation and uterine natural killer cells present in the decidua before preeclampsia development. Furthermore, decidualization defects in the endometrium of women with severe preeclampsia, characterized by impaired cytotrophoblast invasion, were detected at the time of delivery and persisted 5 years after the affected pregnancy. Recently, a maternal deficiency of annexin A2 expression was found to influence aberrant decidualization and shallow cytotrophoblast invasion, suggesting that decidualization resistance, which is a defective endometrial cell differentiation during the menstrual cycle, could underlie shallow trophoblast invasion and the poor establishment of the maternal-fetal interface. Based on these findings, the transcriptional signature in the endometrium that promotes decidualization deficiency could be detected before (or after) conception. This would serve to identify women at risk of developing severe preeclampsia and aid the development of therapies focused on improving decidualization, perhaps also preventing severe preeclampsia. Here, we discuss decidualization deficiency as a contributor to the pathogenesis of pregnancy disorders with particular attention to severe preeclampsia. We also review current diagnostic strategies and discuss future directions in diagnostic methods based on decidualization.
Topics: Annexin A2; Decidua; Early Diagnosis; Endometrium; Female; Humans; Placentation; Pre-Eclampsia; Pregnancy; Trophoblasts
PubMed: 33007270
DOI: 10.1016/j.ajog.2020.09.039 -
American Journal of Reproductive... Dec 2023The endometrium is a unique and highly regenerative tissue with crucial roles during the reproductive lifespan of a woman. As the first site of contact between mother... (Review)
Review
The endometrium is a unique and highly regenerative tissue with crucial roles during the reproductive lifespan of a woman. As the first site of contact between mother and embryo, the endometrium, and its critical processes of decidualization and immune cell recruitment, play a leading role in the establishment of pregnancy, embryonic development, and reproductive capacity. These integral processes are achieved by the concerted actions of steroid hormones and a myriad of growth factor signaling pathways. This review focuses on the roles of the transforming growth factor β (TGFβ) pathway in the endometrium during the earliest stages of pregnancy through the lens of immune cell regulation and function. We discuss how key ligands in the TGFβ family signal through downstream SMAD transcription factors and ultimately remodel the endometrium into a state suitable for embryo implantation and development. We also focus on the key roles of the TGFβ signaling pathway in recruiting uterine natural killer cells and their collective remodeling of the decidua and spiral arteries. By providing key details about immune cell populations and TGFβ signaling within the endometrium, it is our goal to shed light on the intricate remodeling that is required to achieve a successful pregnancy.
Topics: Pregnancy; Female; Humans; Decidua; Transforming Growth Factor beta; Endometrium; Uterus; Embryo Implantation; Signal Transduction
PubMed: 38009061
DOI: 10.1111/aji.13789 -
International Journal of Medical... 2023Recurrent miscarriage (RM) is a pregnancy complication associated with dysregulation of the maternal-fetal interface. We aimed to identify dysfunctional interactions...
Recurrent miscarriage (RM) is a pregnancy complication associated with dysregulation of the maternal-fetal interface. We aimed to identify dysfunctional interactions between trophoblast cells and decidual immune cells in RM. We downloaded single-cell RNA sequencing (scRNA-seq) datasets (GSE214607) from the Gene Expression Omnibus (GEO) datasets for further analysis using the R software. The data comprised of paired placental and decidual tissues, including those from patients diagnosed with RM and matched healthy controls. A total of 22976 cells were identified in 11 cell types, including trophoblasts, immune cells, and other cells. We divided trophoblast cells into three types and analyzed their interactions with decidual immune cells. Additionally, we re-clustered NK&T cells and macrophages, identified differentially expressed genes (DEGs), enriched their functions, and compared the cell interactions with trophoblast cells in each cell type. Our single-cell atlas of the maternal-fetal interface revealed alterations in the cellular organization of the decidua and placenta, cell type-specific transcriptome, and cell communication between immune and non-immune cells in RM, which are critical for illuminating the pathophysiology of RM.
Topics: Pregnancy; Humans; Female; Placenta; Trophoblasts; Decidua; Abortion, Habitual; Pregnancy Trimester, First
PubMed: 37575278
DOI: 10.7150/ijms.86533