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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 -
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 -
Reproductive Sciences (Thousand Oaks,... Apr 2013Preeclampsia (PE) manifested by hypertension and proteinuria complicates 3% to 8% of pregnancies and is a leading cause of fetal-maternal morbidity and mortality... (Review)
Review
Preeclampsia (PE) manifested by hypertension and proteinuria complicates 3% to 8% of pregnancies and is a leading cause of fetal-maternal morbidity and mortality worldwide. It may lead to intrauterine growth restriction, preterm delivery, and long-term sequelae in women and fetuses, and consequently cause socioeconomic burden to the affected families and society as a whole. Balanced immune responses are required for the maintenance of successful pregnancy. Although not a focus of most studies, decidual cells, the major resident cell type at the fetal-maternal interface, have been shown to modulate the local immune balance by interacting with other cell types, such as bone marrow derived-immune cells, endothelial cells, and invading extravillous trophoblasts. Accumulating evidence suggests that an imbalanced innate immunity, facilitated by decidual cells, plays an important role in the pathogenesis of PE. Thus, this review will discuss the role of innate immunity and the potential contribution of decidual cells in the pathogenesis of PE.
Topics: Animals; Decidua; Female; Humans; Immunity, Innate; Killer Cells, Natural; Macrophages; Pre-Eclampsia; Pregnancy
PubMed: 22814099
DOI: 10.1177/1933719112450330 -
BMC Pharmacology & Toxicology Jul 2022As a progesterone receptor antagonist, mifepristone combined with misoprostol is widely used to terminate early pregnancy in clinical practice. It has also been reported...
BACKGROUND
As a progesterone receptor antagonist, mifepristone combined with misoprostol is widely used to terminate early pregnancy in clinical practice. It has also been reported that mifepristone may cause cell death in decidual cells and result in hemorrhage of the decidua and insufficient blood supply. However, little is known about the histological effects of mifepristone on human decidua and chorion.
METHODS
Histological and subcellular structural changes of decidua and chorionic villi from women taking mifepristone at early pregnancy times were examined by Hematoxylin and eosin (H&E) staining and transmission Electron microscope. The expression of apoptosis-related proteins Bax/Bcl-2 was examined by immunohistochemistry.
RESULTS
After 48 h of mifepristone administration, the decidua tissue and chorionic villus structures were altered in women within 39-49 days of gestation and displayed varying degrees of degeneration and necrosis-like features. Apoptotic events were observed in the decidua and chorionic villi of early pregnancy, and mifepristone treatment significantly increases the number of apoptotic cells. The increased apoptotic events were concomitant with the increased expression of Bax and decreased expression of Bcl-2.
CONCLUSION
This study provides evidence that mifepristone induces histological and subcellular changes in decidua and chorionic villi. Mifepristone modulates the relative ratio of Bax/Bcl-2 and the increased apoptosis contributes to the pregnancy termination at early stage of pregnancy.
Topics: Chorionic Villi; Decidua; Female; Humans; Mifepristone; Misoprostol; Pregnancy; Proto-Oncogene Proteins c-bcl-2; bcl-2-Associated X Protein
PubMed: 35869506
DOI: 10.1186/s40360-022-00592-4 -
American Journal of Reproductive... Dec 2021Mucosal-Associated Invariant T (MAIT) cells have been recently identified at the maternal-fetal interface. However, transcriptional programming of decidual MAIT cells in...
PROBLEM
Mucosal-Associated Invariant T (MAIT) cells have been recently identified at the maternal-fetal interface. However, transcriptional programming of decidual MAIT cells in pregnancy remains poorly understood.
METHOD OF STUDY
We employed a multiomic approach to address this question. Mononuclear cells from the decidua basalis and parietalis, and control PBMCs, were analyzed via flow cytometry to investigate MAIT cells in the decidua and assess their transcription factor expression. In a separate study, both decidual and matched peripheral MAIT cells were analyzed using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) coupled with gene expression analysis. Lastly, decidual MAIT cells were stimulated with E.coli and expression of MR1 by antigen presenting cells was measured to evaluate decidual MAIT cell function.
RESULTS
First, we identified MAIT cells in both the decidua basalis and parietalis. CITE-seq, coupled with scRNA-seq gene expression analysis, highlighted transcriptional programming differences between decidual and matched peripheral MAIT cells at a single cell resolution. Transcription factor expression analysis further highlighted transcriptional differences between decidual MAIT cells and non-matched peripheral MAIT cells. Functionally, MAIT cells are skewed towards IFNγ and TNFα production upon stimulation, with E.coli leading to IFNγ production. Lastly, we demonstrate that MR1, the antigen presenting molecule restricting MAIT cells, is expressed by decidual APCs.
CONCLUSION
MAIT cells are present in the decidua basalis and obtain a unique gene expression profile. The presence of MR1 on APCs coupled with in vitro activation by E.coli suggests that MAIT cells might be involved in tissue-repair mechanisms at the maternal-fetal interface.
Topics: Decidua; Female; Flow Cytometry; Humans; Leukocytes; Mucosal-Associated Invariant T Cells; Placenta; Pregnancy
PubMed: 34411378
DOI: 10.1111/aji.13495 -
Seminars in Reproductive Medicine Jan 2010In murine and human pregnancies, embryos implant by attaching to the luminal epithelium and invading into the stroma of the endometrium. Under the influence of the... (Review)
Review
In murine and human pregnancies, embryos implant by attaching to the luminal epithelium and invading into the stroma of the endometrium. Under the influence of the steroid hormones estrogen and progesterone, the stromal cells surrounding the implanting embryo undergo a remarkable transformation event. This process, known as decidualization, is an essential prerequisite for implantation. It comprises morphogenetic, biochemical, and vascular changes driven by the estrogen and progesterone receptors. The development of mutant mouse models lacking these receptors has firmly established the necessity of steroid signaling for decidualization. Genomic profiling of mouse and human endometrium has uncovered a complex yet highly conserved network of steroid-regulated genes that supports decidualization. To advance our understanding of the mechanisms regulating implantation and better address the clinical challenges of infertility and endometrial diseases such as endometriosis, it is important to integrate the information gained from the mouse and human models.
Topics: Animals; Bone Morphogenetic Protein 2; Connexin 43; Decidua; Disease Models, Animal; Embryo Implantation; Endometrium; Female; Homeobox A10 Proteins; Homeodomain Proteins; Humans; Interleukin-11; Mice; Molecular Chaperones; Pregnancy; Receptors, Steroid; Uterine Diseases
PubMed: 20104425
DOI: 10.1055/s-0029-1242989 -
Reproductive Biology and Endocrinology... Feb 2022In early pregnancy, differentiating between a normal intrauterine pregnancy (IUP) and abnormal gestations including early pregnancy loss (EPL) or ectopic pregnancy (EP)...
BACKGROUND
In early pregnancy, differentiating between a normal intrauterine pregnancy (IUP) and abnormal gestations including early pregnancy loss (EPL) or ectopic pregnancy (EP) is a major clinical challenge when ultrasound is not yet diagnostic. Clinical treatments for these outcomes are drastically different making early, accurate diagnosis imperative. Hence, a greater understanding of the biological mechanisms involved in these early pregnancy complications could lead to new molecular diagnostics.
METHODS
Trophoblast and endometrial tissue was collected from consenting women having an IUP (n = 4), EPL (n = 4), or EP (n = 2). Samples were analyzed by LC-MS/MS followed by a label-free proteomics analysis in an exploratory study. For each tissue type, pairwise comparisons of different pregnancy outcomes (EPL vs. IUP and EP vs. IUP) were performed, and protein changes having a fold change ≥ 3 and a Student's t-test p-value ≤ 0.05 were defined as significant. Pathway and network classification tools were used to group significantly changing proteins based on their functional similarities.
RESULTS
A total of 4792 and 4757 proteins were identified in decidua and trophoblast proteomes. For decidua, 125 protein levels (2.6% of the proteome) were significantly different between EP and IUP, whereas EPL and IUP decidua were more similar with only 68 (1.4%) differences. For trophoblasts, there were 66 (1.4%) differences between EPL and IUP. However, the largest group of 344 differences (7.2%) was observed between EP and IUP trophoblasts. In both tissues, proteins associated with ECM remodeling, cell adhesion and metabolic pathways showed decreases in EP specimens compared with IUP and EPL. In trophoblasts, EP showed elevation of inflammatory and immune response pathways.
CONCLUSIONS
Overall, differences between an EP and IUP are greater than the changes observed when comparing ongoing IUP and nonviable intrauterine pregnancies (EPL) in both decidua and trophoblast proteomes. Furthermore, differences between EP and IUP were much higher in the trophoblast than in the decidua. This observation is true for the total number of protein changes as well as the extent of changes in upstream regulators and related pathways. This suggests that biomarkers and mechanisms of trophoblast function may be the best predictors of early pregnancy location and viability.
Topics: Abortion, Spontaneous; Adult; Case-Control Studies; Decidua; Embryo Implantation; Female; Fetal Viability; Gestational Age; Humans; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, First; Pregnancy, Ectopic; Proteome; Signal Transduction; Trophoblasts; Uterus; Young Adult
PubMed: 35189928
DOI: 10.1186/s12958-022-00908-3 -
The International Journal of... 2020The eutherian species evolved an elaborate uterus to allow viviparity. For successful pregnancy, the uterus must not only be differentiated, but must also function... (Review)
Review
The eutherian species evolved an elaborate uterus to allow viviparity. For successful pregnancy, the uterus must not only be differentiated, but must also function optimally and any defects in uterus differentiation and/or function can lead to infertility. The homoebox gene HOXA10 has emerged to be a key player in both uterine development and its optimal functioning in adulthood. Within the Abd-B family, the posterior Hoxa genes play a dominant role in anterio-posterior segmentation of the Müllerian ducts in mammals, with Hoxa10 having a central role in uterine segmentation. In the adult endometrium, HOXA10 is expressed by endometrial cells and is regulated in a cyclic manner under the influence of ovarian steroids. During embryo implantation, expression of HOXA10 is increased in endometrial stromal cells by signals from the embryo to govern stromal cell transformation to decidual cells. Once decidualization is initiated, HOXA10 is rapidly downregulated to activate expression of pro-invasive factors to promote trophoblast invasion. We propose that HOXA10 governs embryo implantation in a three-step process: 1) acquisition of endometrial receptivity, 2) responding to signals from the blastocyst to modify receptive endometrium for decidualization 3) making the decidua conductive for trophoblast invasion and placentation. There is currently ample evidence that expression of HOXA10 is deregulated in a variety of "endometriopathies" such as endometriosis and endometrial cancers. Overall, HOXA10 appears to be the master regulator of endometrial health and a central determinant of fertility in mammals.
Topics: Animals; Cell Differentiation; Decidua; Embryo Implantation; Endometrium; Female; Gene Expression Regulation, Developmental; Homeobox A10 Proteins; Humans; Placentation; Pregnancy
PubMed: 32659011
DOI: 10.1387/ijdb.190120dm -
Asian Pacific Journal of Allergy and... 2008Human pregnancy is a complex process. Placental development depends on the function of secretory molecules produced by placental trophoblast cells as well as by maternal... (Review)
Review
Human pregnancy is a complex process. Placental development depends on the function of secretory molecules produced by placental trophoblast cells as well as by maternal uterine immune cells within the decidua. These decidual immune cells are T cells, natural killer cells, macrophages and dendritic cells. The interactions between the trophoblast cells and the maternal immune cells have an impact on the outcome of the pregnancy. Knowledge about the phenotypes and functions of the maternal immune cells in normal and pathological pregnancies including recurrent spontaneous abortions, preeclampsia and hydatidiform moles may improve our understanding of the immunobiology of the normal pregnancy as a whole and may provide approaches for improving the treatment of pathological pregnancies.
Topics: Abortion, Habitual; Decidua; Female; Humans; Hydatidiform Mole; Immunity, Cellular; Placental Circulation; Placentation; Pre-Eclampsia; Pregnancy; Trophoblasts; Uterus
PubMed: 19054936
DOI: No ID Found -
Placenta Apr 2021Uteroplacental acute atherosis is frequently observed in preeclampsia, and shares features with early atherosclerotic lesions, including artery wall foam cells. The...
INTRODUCTION
Uteroplacental acute atherosis is frequently observed in preeclampsia, and shares features with early atherosclerotic lesions, including artery wall foam cells. The lipid-associated proteins FABP4 (fatty acid binding protein 4), perilipin-2, and LOX-1 (lectin-like oxidized LDL-receptor 1) are involved in atherosclerotic foam cell formation. Increased levels of these proteins have been associated with preeclampsia systemically and in placental tissue. Their role in acute atherosis is yet unidentified. Our aim was to describe the presence of these proteins in acute atherosis, and compare our findings to what is known in early atherosclerotic lesions.
METHODS
Serial sections of decidua basalis tissue from 12 normotensive (4 with acute atherosis) and 23 preeclamptic pregnancies (16 with acute atherosis) were stained with HE and immunostained for CK7, CD68, FABP4, perilipin-2, and LOX-1. Artery wall and perivascular protein expression was assessed in 190 spiral artery sections; 55 with acute atherosis.
RESULTS
Acute atherosis foam cells were commonly positive for perilipin-2 (55%), less often for FABP4 (13%), and never for LOX-1. LOX-1 was frequently observed in intramural trophoblasts of normal spiral arteries. Perivascularly, LOX-1 positivity of decidual stromal cells surrounding arteries with acute atherosis was significantly increased as compared to arteries lacking acute atherosis (38% vs. 15%, p < 0.001).
DISCUSSION
We found that perilipin-2 and FABP4 are expressed by acute atherosis foam cells, similar to atherosclerosis, supporting possible shared pathways for foam cell generation. Unlike atherosclerosis, LOX-1 is not present in acute atherosis, possibly explained by pregnancy-specific routes to decidua basalis foam cell generation.
Topics: Adult; Atherosclerosis; Decidua; Fatty Acid-Binding Proteins; Female; Foam Cells; Humans; Perilipin-2; Scavenger Receptors, Class E
PubMed: 33725567
DOI: 10.1016/j.placenta.2021.03.001