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International Journal of Biological... 2020The survival and development of a semi-allogenic fetus during pregnancy require special immune tolerance microenvironment at the maternal fetal interface. During the... (Review)
Review
The survival and development of a semi-allogenic fetus during pregnancy require special immune tolerance microenvironment at the maternal fetal interface. During the establishment of a successful pregnancy, the endometrium undergoes a series of changes, and the extracellular matrix (ECM) breaks down and remodels. Collagen is one of the most abundant ECM. Emerging evidence has shown that collagen and its fragment are expressed at the maternal fetal interface. The regulation of expression of collagen is quite complex, and this process involves a multitude of factors. Collagen exerts a critical role during the successful pregnancy. In addition, the abnormal expressions of collagen and its fragments are associated with certain pathological states associated with pregnancy, including recurrent miscarriage, diabetes mellitus with pregnancy, preeclampsia and so on. In this review, the expression and potential roles of collagen under conditions of physiological and pathological pregnancy are systematically discussed.
Topics: Collagen; Decidua; Female; Gene Expression Regulation; Humans; Maternal-Fetal Exchange; Placenta; Pregnancy
PubMed: 32549767
DOI: 10.7150/ijbs.45586 -
Fertility and Sterility Mar 2023To define the decidual microenvironment in euploid and aneuploid missed abortions and elective termination of pregnancies. (Observational Study)
Observational Study
OBJECTIVE
To define the decidual microenvironment in euploid and aneuploid missed abortions and elective termination of pregnancies.
DESIGN
Prospective, multicenter, observational study.
SETTING
Tertiary hospital and descriptive analysis of transcriptomic data.
PATIENT(S)
A total of 34 patients experienced abortions, including 6 women who underwent elective terminations of pregnancy of unplanned pregnancies and 28 cases with missed abortions. All patients underwent their operations from Sep, 2021 to Sep, 2022.
INTERVENTION(S)
All women underwent villous copy number variation sequencing. Meanwhile, single-cell RNA sequencing were performed in the decidual tissues of 16 women, and reverse transcription quantitative polymerase chain reaction were performed in the decidual tissues of 18 women.
MAIN OUTCOME MEASURE(S)
Single-cell RNA sequencing was used to explore the changes in the microenvironment of decidual tissues in abortions.
RESULT(S)
Single-cell RNA sequencing indicated that the microenvironment of the decidual tissue of the missed-abortion group was altered, and that the stromal cells (SCs), natural killer cells, macrophages, and epithelial cells all reflected functional imbalances compared with the elective terminations of pregnancy group. We also noted a correlation between the proportion of senescent SCs and chromosomal abnormalities in missed-abortion embryos. The proportion of senescent decidual SCs in the decidual tissue of missed-abortion patients with common chromosomal abnormalities of the fetus was higher, and this was not conducive to fetal growth and was closely related to missed abortion. In addition, we ascertained that the strength of the HLA-KIR interaction between NK1 and NK2 subsets and non-senescent stromal cell subsets in the missed abortion decidual tissues was weakened, potentially playing a role in the occurrence of missed abortion.
CONCLUSION(S)
The decidualization of SCs in the missed-abortion decidual tissues was impaired, the clearance of senescent SCs by NK cells was weakened, the killing toxicity of non-senescent SCs was enhanced, macrophages were insufficiently resident at the maternal-fetal interface, and epithelial cell differentiation was unbalanced-all creating a maternal microenvironment that was not conducive to fetal growth. We posit that interfering with the expression of dysregulated genes in the missed-abortion decidual tissues and reversing the maternal microenvironment might constitute an effective means toward improving the clinical outcome of missed abortions. Intriguingly, we observed a correlation between stromal cell senescence and embryonic chromosomal abnormalities. Thus, we hypothesize that the DIO2 marker of senescent SCs can be used as a risk indicator for the occurrence of missed miscarriages with chromosomal abnormalities of the embryos, and that it can be applied to guide the clinical diagnosis and treatment of recurrent abortion.
CLINICAL TRIAL REGISTRATION NUMBER
NCT04425317.
Topics: Female; Humans; Pregnancy; Abortion, Habitual; Abortion, Missed; Chromosome Aberrations; Decidua; DNA Copy Number Variations; Prospective Studies; Iodothyronine Deiodinase Type II
PubMed: 36528108
DOI: 10.1016/j.fertnstert.2022.12.016 -
Biology of Reproduction Aug 2022Uterine dysfunctions lead to fertility disorders and pregnancy complications. Normal uterine functions at pregnancy depend on crosstalk among multiple cell types in...
Uterine dysfunctions lead to fertility disorders and pregnancy complications. Normal uterine functions at pregnancy depend on crosstalk among multiple cell types in uterine microenvironments. Here, we performed the spatial transcriptomics and single-cell RNA-seq assays to determine local gene expression profiles at the embryo implantation site of the mouse uterus on pregnancy day 7.5 (D7.5). The spatial transcriptomic annotation identified 11 domains of distinct gene signatures, including a mesometrial myometrium, an anti-mesometrial myometrium, a mesometrial decidua enriched with natural killer cells, a vascular sinus zone for maternal vessel remodeling, a fetal-maternal interface, a primary decidual zone, a transition decidual zone, a secondary decidual zone, undifferentiated stroma, uterine glands, and the embryo. The scRNA-Seq identified 12 types of cells in the D7.5 uterus including three types of stromal fibroblasts with differentiated and undifferentiated markers, one cluster of epithelium including luminal and glandular epithelium, mesothelium, endothelia, pericytes, myelomonocytic cell, natural killer cells, and lymphocyte B. These single-cell RNA signatures were then utilized to deconvolute the cell-type compositions of each individual uterine microenvironment. Functional annotation assays on spatial transcriptomic data revealed uterine microenvironments with distinguished metabolic preferences, immune responses, and various cellular behaviors that are regulated by region-specific endocrine and paracrine signals. Global interactome among regions is also projected based on the spatial transcriptomic data. This study provides high-resolution transcriptome profiles with locality information at the embryo implantation site to facilitate further investigations on molecular mechanisms for normal pregnancy progression.
Topics: Animals; Decidua; Embryo Implantation; Epithelium; Female; Killer Cells, Natural; Mice; Myometrium; Pregnancy; Transcriptome; Uterus
PubMed: 35357464
DOI: 10.1093/biolre/ioac061 -
Seminars in Immunopathology Nov 2022The conception of how the immune system is organized has been significantly challenged over the last years. It became evident that not all lymphocytes are mobile and... (Review)
Review
The conception of how the immune system is organized has been significantly challenged over the last years. It became evident that not all lymphocytes are mobile and recirculate through secondary lymphoid organs. Instead, subsets of immune cells continuously reside in tissues until being reactivated, e.g., by a recurring pathogen or other stimuli. Consequently, the concept of tissue-resident immunity has emerged, and substantial evidence is now available to support its pivotal function in maintaining tissue homeostasis, sensing challenges and providing antimicrobial protection. Surprisingly, insights on tissue-resident immunity in the barrier tissues of the female reproductive tract are sparse and only slowly emerging. The need for protection from vaginal and amniotic infections, the uniqueness of periodic tissue shedding and renewal of the endometrial barrier tissue, and the demand for a tailored decidual immune adaptation during pregnancy highlight that tissue-resident immunity may play a crucial role in distinct compartments of the female reproductive tract. This review accentuates the characteristics of tissue-resident immune cells in the vagina, endometrium, and the decidua during pregnancy and discusses their functional role in modulating the risk for infertility, pregnancy complications, infections, or cancer. We here also review data published to date on tissue-resident immunity in the male reproductive organs, which is still a largely uncharted territory.
Topics: Female; Humans; Male; Pregnancy; Endometrium; Homeostasis; Immunity, Innate; Infertility; Lymphocytes; Genitalia, Female; Genitalia, Male
PubMed: 35488095
DOI: 10.1007/s00281-022-00934-8 -
Biomolecules Sep 2022Several factors are important for implantation and subsequent placentation in the endometrium, including immunity, angiogenesis, extracellular matrix, glucose... (Review)
Review
Several factors are important for implantation and subsequent placentation in the endometrium, including immunity, angiogenesis, extracellular matrix, glucose metabolism, reactive oxidative stress, and hormones. The involvement or abnormality of these factors can impair canonical decidualization. Unusual decidualization can lead to perinatal complications, such as disruption of trophoblast invasion. Drastic changes in the morphology and function of human endometrial stromal cells (hESCs) are important for decidualization of the human endometrium; hESCs are used to induce optimal morphological and functional decidualization in vitro because they contain estrogen and progesterone receptors. In this review, we will focus on the studies that have been conducted on hESC decidualization, including the results from our laboratory.
Topics: Cells, Cultured; Decidua; Estrogens; Female; Glucose; Humans; Pregnancy; Receptors, Progesterone; Stromal Cells
PubMed: 36139114
DOI: 10.3390/biom12091275 -
Frontiers in Immunology 2020Immunological adaptations in pregnancy allow maternal tolerance of the semi-allogeneic fetus but also increase maternal susceptibility to infection. At implantation, the... (Review)
Review
Immunological adaptations in pregnancy allow maternal tolerance of the semi-allogeneic fetus but also increase maternal susceptibility to infection. At implantation, the endometrial stroma, glands, arteries and immune cells undergo anatomical and functional transformation to create the decidua, the specialized secretory endometrium of pregnancy. The maternal decidua and the invading fetal trophoblast constitute a dynamic junction that facilitates a complex immunological dialogue between the two. The decidual and peripheral immune systems together assume a pivotal role in regulating the critical balance between tolerance and defense against infection. Throughout pregnancy, this equilibrium is repeatedly subjected to microbial challenge. Acute viral infection in pregnancy is associated with a wide spectrum of adverse consequences for both mother and fetus. Vertical transmission from mother to fetus can cause developmental anomalies, growth restriction, preterm birth and stillbirth, while the mother is predisposed to heightened morbidity and maternal death. A rapid, effective response to invasive pathogens is therefore essential in order to avoid overwhelming maternal infection and consequent fetal compromise. This sentinel response is mediated by the innate immune system: a heritable, highly evolutionarily conserved system comprising physical barriers, antimicrobial peptides (AMP) and a variety of immune cells-principally neutrophils, macrophages, dendritic cells, and natural killer cells-which express pattern-receptors that detect invariant molecular signatures unique to pathogenic micro-organisms. Recognition of these signatures during acute infection triggers signaling cascades that enhance antimicrobial properties such as phagocytosis, secretion of pro-inflammatory cytokines and activation of the complement system. As well as coordinating the initial immune response, macrophages and dendritic cells present microbial antigens to lymphocytes, initiating and influencing the development of specific, long-lasting adaptive immunity. Despite extensive progress in unraveling the immunological adaptations of pregnancy, pregnant women remain particularly susceptible to certain acute viral infections and continue to experience mortality rates equivalent to those observed in pandemics several decades ago. Here, we focus specifically on the pregnancy-induced vulnerabilities in innate immunity that contribute to the disproportionately high maternal mortality observed in the following acute viral infections: Lassa fever, Ebola virus disease (EVD), dengue fever, hepatitis E, influenza, and novel coronavirus infections.
Topics: Adaptive Immunity; COVID-19; Coronavirus Infections; Decidua; Dengue; Female; Hemorrhagic Fever, Ebola; Hepatitis E; Humans; Immune Tolerance; Immunity, Innate; Influenza, Human; Lassa Fever; Pandemics; Placenta; Pneumonia, Viral; Pregnancy; Virus Diseases
PubMed: 33101294
DOI: 10.3389/fimmu.2020.572567 -
International Journal of Molecular... Oct 2019Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy,... (Review)
Review
Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy, but is also a significant reproductive disorder affecting around 5% of couples desiring a child. The current knowledge on RPL is largely incomplete, since nearly 50% of RPL cases are still classified as unexplained. Emerging evidence indicates that the endometrium is a key tissue involved in the correct immunologic dialogue between the mother and the conceptus, which is a condition essential for the proper establishment and maintenance of a successful pregnancy. The immunologic events occurring at the maternal-fetal interface within the endometrium in early pregnancy are extremely complex and involve a large array of immune cells and molecules with immunoregulatory properties. A growing body of experimental studies suggests that endometrial immune dysregulation could be responsible for several, if not many, cases of RPL of unknown origin. The present article reviews the major immunologic pathways, cells, and molecular determinants involved in the endometrial dysfunction observed with specific application to RPL.
Topics: Abortion, Habitual; Cytokines; Decidua; Dendritic Cells; Embryo, Mammalian; Endometrium; Female; Humans; Killer Cells, Natural; Macrophages; Pregnancy; T-Lymphocytes, Regulatory
PubMed: 31717776
DOI: 10.3390/ijms20215332 -
Nutrients Nov 2023Though firstly identified in cerebral folate deficiency, autoantibodies against folate receptors (FRAbs) have been implicated in pregnancy complications such as... (Review)
Review
Though firstly identified in cerebral folate deficiency, autoantibodies against folate receptors (FRAbs) have been implicated in pregnancy complications such as miscarriage; however, the underlying mechanism needs to be further elaborated. FRAbs can be produced via sensitization mediated by folate-binding protein as well as gene mutation, aberrant modulation, or degradation of folate receptors (FRs). FRAbs may interfere with folate internalization and metabolism through blocking or binding with FRs. Interestingly, different types of FRs are expressed on trophoblast cells, decidual epithelium or stroma, and macrophages at the maternal-fetal interface, implying FRAbs may be involved in the critical events necessary for a successful pregnancy. Thus, we propose that FRAbs may disturb pregnancy establishment and maintenance by modulating trophoblastic biofunctions, placental development, decidualization, and decidua homeostasis as well as the functions of macrophages. In light of these findings, FRAbs may be a critical factor in pathological pregnancy, and deserve careful consideration in therapies involving folic acid supplementation for pregnancy complications.
Topics: Pregnancy; Female; Humans; Abortion, Spontaneous; Placenta; Autoantibodies; Folic Acid; Pregnancy Complications; Decidua; Folate Receptor 2
PubMed: 38068740
DOI: 10.3390/nu15234882 -
Archivum Immunologiae Et Therapiae... Oct 2019Macrophages (MФs) are the leukocytes produced from differentiation of monocytes and are located in almost all tissues of human body. They are involved in various... (Review)
Review
Macrophages (MФs) are the leukocytes produced from differentiation of monocytes and are located in almost all tissues of human body. They are involved in various processes, such as phagocytosis, innate and adaptive immunity, proinflammatory (M1) and anti-inflammatory (M2) activity, depending on the tissue microenvironment. They play a crucial role in pregnancy, and their dysfunction or alteration of polarity is involved in pregnancy disorders, like preeclampsia, recurrent spontaneous abortion, infertility, intrauterine growth restriction, and preterm labor. About 50-60% of decidual leukocytes are natural killer (NK) cells followed by MФs (the second largest population). MФs are actively involved in trophoblast invasion, tissue and vascular remodeling during early pregnancy, besides their role as major antigen-presenting cells in the decidua. These cells have different phenotypes and polarities in different stages of pregnancy. They have also been observed to enhance tumor growth by their anti-inflammatory activity (M2 type) and prevent immunogenic rejection. Targeted alteration of polarity (M1-M2 or vice versa) could be a major focus in the future treatment of pregnancy complications. This review is focused on the role of MФs in pregnancy, their involvement in pregnancy disorders, and decidual MФs as possible therapeutic targets for the treatment of pregnancy complications.
Topics: Animals; Decidua; Embryo Implantation; Female; Humans; Immune Tolerance; Macrophages; Pregnancy; Pregnancy Complications; Vascular Endothelial Growth Factors
PubMed: 31286151
DOI: 10.1007/s00005-019-00552-7 -
Frontiers in Immunology 2020During pregnancy, the placenta forms the anatomical barrier between the mother and developing fetus. Infectious agents can potentially breach the placental barrier... (Review)
Review
During pregnancy, the placenta forms the anatomical barrier between the mother and developing fetus. Infectious agents can potentially breach the placental barrier resulting in pathogenic transmission from mother to fetus. Innate immune responses, orchestrated by maternal and fetal cells at the decidual-placental interface, are the first line of defense to avoid vertical transmission. Here, we outline the anatomy of the human placenta and uterine lining, the decidua, and discuss the potential capacity of pathogen pattern recognition and other host defense strategies present in the innate immune cells at the placental-decidual interface. We consider major congenital infections that access the placenta from hematogenous or decidual route. Finally, we highlight the challenges in studying human placental responses to pathogens and vertical transmission using current experimental models and identify gaps in knowledge that need to be addressed. We further propose novel experimental strategies to address such limitations.
Topics: Animals; Decidua; Disease Models, Animal; Female; Humans; Immunity, Innate; Infections; Infectious Disease Transmission, Vertical; Placenta; Pregnancy
PubMed: 33013876
DOI: 10.3389/fimmu.2020.02070