Decidual Cells Research Articles

The Circadian Clock, Nutritional Signals and Reproduction: A Close Relationship.

The circadian rhythm, which is necessary for reproduction, is controlled by clock genes. In the mouse uterus, the oscillation of the circadian clock gene has been observed. The transcription of the core clock gene period (Per) and cryptochrome (Cry) is activated by the heterodimer of the transcription factor circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein-1 (Bmal1). By binding to E-box sequences in the promoters of Per1/2 and Cry1/2 genes, the CLOCK-BMAL1 heterodimer promotes the transcription of these genes. Per1/2 and Cry1/2 form a complex with the Clock/Bmal1 heterodimer and inactivate its transcriptional activities. Endometrial BMAL1 expression levels are lower in human recurrent-miscarriage sufferers. Additionally, it was shown that the presence of BMAL1-depleted decidual cells prevents trophoblast invasion, highlighting the importance of the endometrial clock throughout pregnancy. It is widely known that hormone synthesis is disturbed and sterility develops in Bmal1-deficient mice. Recently, we discovered that animals with uterus-specific Bmal1 loss also had poor placental development, and these mice also had intrauterine fetal death. Furthermore, it was shown that time-restricted feeding controlled the uterine clock's circadian rhythm. The uterine clock system may be a possibility for pregnancy complications, according to these results. We summarize the most recent research on the close connection between the circadian clock and reproduction in this review.

DIFFUSE ECTOPIC DECIDUOSIS MIMICKING AS PERITONEAL CARCINOMATOSIS: A CASE REPORT OF A YOUNG FEMALE WITH MULTIPLE SEROSAL AND OMENTAL NODULES FOUND DURING A CAESARIAN SECTION

Background & Objectives: Ectopic deciduosis refers to an abnormal occurrence of decidual tissue beyond the endometrium, predominantly on the surface of the uterus, fallopian tubes, ovaries and omentum. Diffuse omental and perito-neal involvement is a perplexing manifestation that may mimic peritoneal carcinomatosis. It is not accompanied by any symptoms and complications in most of the cases and does not require treatment. However, rarely it can present with acute abdomen or imitate peritoneal malignancy and, thus, associated with diagnostic difficulties and unnecessary interventions. Aim of this case report is to describe a rare case of peritoneal deciduosis in a young female, found incidentally, during a caesarean section, mimicking metastatic nodules. Afutile hysterec-tomy along with omentectomy was performed.
 Methods: A case of diffuse ectopic deciduosis mimicking as peritoneal carcinomatosis in a 29 years young female with full term pregnancy was found during a lower segment caesarian section, undertaken in a tertiary care teaching hospital of Lahore, Pakistan. The histopathological diagnosis was based on common technique of paraffin embedding and hematoxylin-eosin staining along with ancillary immune-histochemical evaluation.
 Results: Histopathological evaluation showed ectopic decidual tissue consisted of solid nests and loosely cohesive aggregates; large polygonal cells with abundant granular eosinophilic cytoplasm; sharply defined cell borders, bland nuclei with dispersed chromatin and single conspicuous nucleoli on the surface of uterus and in omental fat. Weak staining for CD30 was observed in the decidual cell cytoplasm and negative staining for CK and Calretinin in decidual cells was found. Calretinin and CK highlight benign mesothelial cells and help to rule out differentials of mesothelioma and metastatic carcinoma.
 Conclusion: Peritoneal deciduosis represents a rare entity and it is important to consider this condition in patients, especially in pregnant women, to prevent unnecessary intervention In addition, distinguishing this condition from malignant neoplasms will help in deciding correct treatment options.

The emerging role of TET enzymes in the immune microenvironment at the maternal-fetal interface during decidualization and early pregnancy.

A dysregulated immune microenvironment at the maternal-fetal interface in early pregnancy may lead to early pregnancy loss, fetal growth restriction, and preeclampsia. However, major questions about how epigenetic modifications regulate the immune microenvironment during the decidualization process and embryo implantation remain unanswered. DNA methylation, the main epigenetic mechanism involved in the endometrial cycle, is crucial for specific transcriptional networks associated with endometrial stromal cell (ESC) proliferation, hormone response, decidualization, and embryo implantation. Ten-eleven translocation (TET) enzymes, responsible for catalyzing the conversion of 5-methylcytosine to 5-hydroxymethylcyosine, 5-formylytosine, and 5-carboxylcyosine to achieve the DNA demethylation process, appear to play a critical role in decidualization and embryo implantation. Here, we provide a comprehensive view of their structural similarities and the common mechanism of regulation in the microenvironment at the maternal-fetal interface during decidualization and early pregnancy. We also discuss their physiological role in the decidual immune microenvironment. Finally, we propose a key hypothesis regarding TET enzymes at the maternal-fetal interface between decidual immune cells and ESCs. Future work is needed to elucidate their functional role and examine therapeutic strategies targeting these enzymes in pregnancy-related disease preclinical models, which would be of great value for future implications in disease diagnosis or treatment.

Effects of the SPI/lncRNA NEAT1 Axis on Functions of Trophoblast and Decidual Cells in Patients with Recurrent Miscarriage

Recurrent miscarriage (RM) is a frustrating and complex pregnancy disorder and long noncoding RNAs (lncRNAs) modulate susceptibility to RM. This study expounded on the role of specificity protein 1 (SP1) in functions of chorionic trophoblast and decidual cells via regulating lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1). Chorionic villus tissues and decidual tissues of RM patients and normal pregnant women were collected. Real-time quantitative polymerase chain reaction and Western blotting revealed that SP1 and NEAT1 were downregulated in trophoblast and decidual tissues of RM patients, and the Pearson correlation analysis detected that they were positively correlated in expression level. Chorionic trophoblast and decidual cells of RM patients were isolated and intervened by vectors over-expressing SP1 or NEAT1 siRNAs. Thereafter, the cell counting kit-8, Transwell, flow cytometry assays detected that SP1 overexpression accelerated trophoblast cell proliferation, invasion, and migration, meanwhile, enhancing decidual cell proliferation while repressed apoptosis. Next, the dual-luciferase and Chromatin immunoprecipitation assays showed that SP1 bound to the NEAT1 promoter region and further activated NEAT1 transcription. Silencing NEAT1 reversed the efforts of SP1 overexpression on the functions of trophoblast and decidual cells. Overall, SP1 activated NEAT1 transcription, accelerating trophoblast cell proliferation, invasion, and migration and mitigating decidual cell apoptosis.

Role of SOX9 and Hif-1α expression in placentas of patients with HELLP.

In this study, we investigated the immunohistochemical staining of SRY-box transcription factor 9 (SOX9) and Hif-1α expression in placentas of pregnant woman with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. Placentas of 20 normotensive and 20 women with HELLP syndrome were processed for routine histological tissue processing. The biochemical and clinical parameters of patients were recorded. Placentas were stained with hematoxylin-eosin and SOX9 and Hif-1α immunostaining. Normotensive placentas showed normal histology of placenta, however placentas of HELLP syndrome showed intense thrombosis, thinning of the villi membrane and vascular dilatation. In placentas of normotensive patients, SOX9 reaction was immunohistochemically negative, however placentas of HELLP group showed SOX9 expression in decidual cells, and syncytial regions of floating villi and inflammatory cells. In placentas of normotensive patients, Hif-1α reaction was mainly negative in vessels and connective tissue cells. Placentas of HELLP group showed increased Hif-1α expression in decidual cell and especially inflammatory cells in the maternal region. Hif-1α and SOX9 proteins can be used as a marker to show severity of preeclampsia and regulation of cell proliferation and angiogenesis during placental development.

Crosstalk between Placental Trophoblast and Decidual Immune Cells in Recurrent Miscarriage.

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.

Study of histopathological changes and the levels of TNF-α in Preterm Preeclamptic women

Preeclampsia (PE) is a significant contributor to maternal morbidity and mortality that manifests as new-onset hypertension after 20 weeks of pregnancy with signs of uteroplacental or maternal organ dysfunction or proteinuria. This condition is linked to intrauterine growth restriction, preterm birth, placental abruption, fetal distress, and fetal death in utero. The findings of the recent study can be summed up as follows: Hematoxylin and eosin staining of placenta tissues revealed a significant area of calcification in the villous stroma. Additionally, increased collagen fibers around blood vessels and varying degrees of mononuclear cell infiltration are caused by capillary and vein congestion. The Masson's Trichrome stain revealed deposited fibrin between decidual cells and extra-villous cytotrophoblasts, which were surrounded by mature intermediate and terminal villi. Congestion of veins with increased fibrin deposits around veins and arterial vessels with increased fibrocytes When the data was statistically analyzed, it was discovered that PE pregnant women had significantly p<0.05 higher levels of serum TNF- α , than normotensive women ( NT ). Finally, the study found a link between preterm PE and women's pregnancy, as well as histopathologic and immunological parameters in preterm PE and NT women.

Expression dynamics of Crry at the implantation sites in normal pregnancy and response against miscarriage induction.

In mammals, immune tolerance against fetal tissue has been established for normal pregnancy progression. It is known that Crry regulates complemental activity to prevent injury of the mouse embryo and extra-embryonic tissue. This study aimed to examine the expression appearance and normal localization sites of Crry in the mouse placenta. Also, the emergency responses of Crry were verified at the time of experimental miscarriage induction. Moreover, we investigated an existing similar protein of Crry in animal placentas other than mice. Crry expression level showed a peak at day 8.5 of pregnancy. Trophoblast giant cells and decidual cells indicated a positive reaction to anti-Crry antibody. After treatments of interferon-γ, Crry expression was increased significantly in the survived implantation sites as compared with the controls. However, there was no significant difference in the miscarriage-initiated sites. It disclosed that Crry distributes from the early to middle periods of the placentas and involves complement regulation at the extraembryonic tissue and decidua basalis. Crry also showed an ability to respond to risk against external initiation for urgent miscarriage. Finally, we found anti-mouse Crry antibody-bound proteins in the placenta of many animals. It suggests a potency of Crry to make an environment of immune tolerance in many types of mammal placentas.

Stemness maintenance of stem cells derived from human exfoliated deciduous teeth (SHED) in 3D spheroid formation through the TGF-β/Smad signaling pathway.

Mesenchymal stem cells (MSCs) have shown great potential as important therapeutic tools for dental pulp tissue engineering, with the maintenance and enhancement of their stemness being crucial for successful therapeutic application in vivo and three-dimensional (3D) spheroid formation considered a reliable technique for enhancing their pluripotency. Human exfoliated deciduous tooth stem cells (SHED) were cultured in a low attachment plate to form aggregates for five days. Then, the resulting spheroids were analyzed for pluripotent marker expression, paracrine secretory function, proliferation, signaling pathways involved, and distribution of key proteins within the spheroids. The results indicated that 3D spheroid formation significantly increased the activation of the transforming growth factor beta (TGF-β)/Smad signaling pathway and upregulated the secretion and mRNA expression levels of TGF-β, which in turn enhanced the expression of pluripotency markers in SHED spheroids. The activation of the TGF-β/Smad signaling pathway through 3D spheroid formation was found to preserve the stemness properties of SHED. Thus, understanding the mechanisms behind pluripotency maintenance of SHED culture through 3D spheroid formation could have implications for the therapeutic application of MSCs in regenerative medicine and tissue engineering.

Research progress in the mechanism of action of NK cell-related receptors during recurrent spontaneous abortion

Recurrent spontaneous abortion (RSA) refers to multiple spontaneous abortions with the same sexual partner; In 2020, Chinese expert consensus suggested that it should be defined as the loss of the embryo or fetus before 28 weeks of gestation with the same sexual partner for two or more times in a row, including the biochemical pregnancy that occurred several times in a row. The pathogenesis of RSA is complex and diverse. At present, the pathogenesis factors have been widely recognized by the industry, including genetic factors, endocrine factors, anatomical abnormalities, infectious factors and immune factors. Among them, the role of immune factors such as T lymphocytes, dendritic cells and natural killer cells (NK) in the occurrence and development of RSA has attracted wide attention, especially NK cells. NK cells are an important part of human immune system. The specific surface molecules of Decidual natural killer cell (dNK) play an immunomodulatory role in the invasion of trophoblast cells and the remodeling of uterine spiral artery during pregnancy, which is particularly important in the early gestation period. The function of dNK cells is tightly regulated by a balance between activation and inhibition signals transmitted by the various family of receptors (NK cell receptors, NKRS) that DNK cells express. In this paper, the existing research progress of decidual NK cells on the mechanism of its receptors in the process of recurrent spontaneous abortion will be reviewed as follows.

Метаболическая регуляция функций натуральных киллеров

Changes in the body metabolism affect the metabolic and functional activity of cells of the immune system. Pregnancy is characterized by changes in hormone production, basal metabolism, immunoreactivity, increase of fat mass. During pregnancy, NK cells acquire a regulatory phenotype, migrate to the uterus and become the dominant subpopulation of lymphocytes in uterus (decidual NK), which is necessary to maintain the invasive syncytiotrophoblast growth. This transformation into decidual NK cells is accompanied by increased glucose consumption and a predominant transition from oxidative phosphorylation to glycolysis. The key molecules involved in controlling the implementation of metabolic programs of NK cells are the target for rapamycin in mammalian cells (mTOR) and AMP-activated protein kinase (AMPK). The modularization of mTOR and AMPK activity by various agents (hormones, cytokines) during pregnancy determines the metabolic reprogramming of the NK cell phenotype and functions. The study of the metabolic regulation of the NK functional activity is necessary to increase the effectiveness of NK cell therapy.

An optimized proteomics-based approach to estimate blood contamination and cellular heterogeneity of frozen placental tissue

IntroductionArchived human placental tissue specimens are vital for studying placenta pathophysiology and toxicology. Proteomics analysis of placental tissue provides mechanistic and translational information, but the highly perfused and heterogenous nature of the placenta creates confounding technical variability. In this study, we developed an optimized proteomics-based approach to address the technical variability of proteomics data by normalizing blood contamination and cellular heterogeneity of archived placenta samples. MethodsPlacenta samples (n = 99) were homogenized, digested using trypsin, and analyzed by liquid chromatography mass-spectrometry. Label-free quantification (LFQ) intensities of the proteins were analyzed for their correlation with blood (albumin) and placenta (aromatase) markers. Proteins that positively correlated with albumin and negatively correlated with aromatase or vice versa were considered blood and placental proteins, respectively. Next, the cellular heterogeneity of individual placenta samples was evaluated by quantifying specific cellular markers of cytotrophoblasts, syncytiotrophoblasts, extravillous trophoblasts, fibroblasts, Hofbauer cells, and decidual cells. ResultsWe found that placental proteins were contaminated by 41 to 85% blood proteins. Analysis of cellular markers confirmed syncytiotrophoblasts as the major cell type in placenta (i.e., 41 ± 9% of all cell types). Two samples showed distinct cell compositions with higher levels of the extravillous trophoblasts and decidual cells. DiscussionIn summary, the optimized proteomics-based approach to estimate blood contamination and cellular heterogeneity of placental tissues has the potential to address technical variability in placenta proteomics analysis, which can be extended to other highly perfused and heterogenous tissues.

Role of Uterine Telocytes During Pregnancy

Abstract Endometrial remolding and angiogenesis are critical events that occur during pregnancy in order to establish uteroplacental vascular communication. This study investigated the role of uterine telocytes (TCs) in pregnancy. We analyzed the distribution of TCs and morphological changes in the endometrium of the gravid rabbit uterus at different stages of pregnancy: after ovulation, pre-implantation (day 7), post-implantation (days 8 and 9), and mid-pregnancy (day 14) and late (days 21–28) pregnancy. TCs gradually increased with the progression of pregnancy. They had distinctive telopodes (TPs) and podoms, with intranucleolar chromatin. The TCs established contact with decidual cells, growing a glandular epithelium, blood vessels, and immune cells, such as lymphocytes, neutrophils, and macrophages. The TCs underwent morphological changes at the post-implantation phase. They acquired thick and voluminous TPs, formed an extensive three-dimensional (3D) labyrinth at mid-pregnancy, and exhibited irregular-shaped nuclei and a dilated rough endoplasmic reticulum at late pregnancy. They also acquired a convoluted contour-formed complex network. Scanning electron microscopy (SEM) showed an extensive 3D network in the endometrium, forming a condensed sheath at late pregnancy. Transmission electron microscopy and SEM detected fenestrated TPs, and TCs were identified by CD34 and vascular endothelial growth factor expression. TCs also expressed matrix metalloproteinase-9 and transforming growth factor beta-1. Results suggested that TCs might play an essential role in maternal placenta formation, especially decidualization, regulation of uterine gland development, and neovascularization of maternal uterine blood vessels.

Transcriptomic profiling of canine decidualization and effects of antigestagens on decidualized dog uterine stromal cells

Maternal-stroma derived decidual cells, the only cell population in the canine placenta expressing the nuclear progesterone (P4) receptor (PGR), are crucial for the maintenance of canine pregnancy. Decreased circulating progesterone (P4) levels, or blockage of PGR function with antigestagens, terminate canine pregnancy. As an in vitro model for canine decidualization, dog uterine stromal (DUS) cells can be decidualized in vitro with cAMP. The antigestagens aglepristone and mifepristone ablate the expression of decidualization markers in DUS cells (e.g., PGR, PRLR, IGF1 or PTGES). Here, the transcriptome profile of DUS cells was investigated to acquire deeper insights into decidualization-associated changes. Additionally, effects mediated by antigestagens (competitive PGR blockers) in decidualized cells were assessed. Decidualization led to the upregulation of 1841 differentially expressed genes (DEGs, P and FDR < 0.01) involved in cellular proliferation and adhesion, mesenchymal-epithelial transition, extracellular matrix organization, and vaso- and immunomodulation. The 1475 DEGs downregulated after decidualization were mostly associated with apoptosis and cell migration. In decidualized DUS cells, aglepristone modulated 1400 DEGs and mifepristone 1558 DEGs. Interestingly, around half of the identified DEGs were modulated by only one of the antigestagens. In all cases, however, PGR-blockage was mainly associated with an inversion of several decidualization-induced effects. Comparison between antigestagen-mediated effects and transcriptional changes in the canine placenta at term allowed the identification of 191 DEGs associated with diminished cell proliferation and adhesion, and vascular and immune modulation. This study emphasizes the importance of P4/PGR signaling for decidual cell function, providing new insights into the maintenance of canine pregnancy.

Chlamydia trachomatis antigen induces TLR4-TAB1-mediated inflammation, but not cell death, in maternal decidua cells.

During gestation, the decidua is an essential layer of the maternal-fetal interface, providing immune support and maintaining inflammatory homeostasis. Although Chlamydia (C.) trachomatis is associated with adverse pregnancy outcomes the pathogenic effects on maternal decidua contributing to adverse events are not understood. This study examined how C. trachomatis antigen affects cell signaling, cell death, and inflammation in the decidua. Primary decidua cells (pDECs) from term, not-in-labor, fetal membrane-decidua were cultured using the following conditions: (1) control - standard cell culture conditions, (2) 100ng/ml or (3) 200ng/ml of C. trachomatis antigen to model decidual cell infection in vitro. Differential expression of Toll-like receptor (TLR) 4 (receptor for C. trachomatis antigen), signaling pathway markers phosphorylated TGF-Beta Activated Kinase 1 (PTAB1), TAB1, phosphorylated p38 mitogen-activated protein kinases (Pp38 MAPK), and p38 MAPK (western blot), decidual cell apoptosis and necrosis (flow cytometry), and inflammation (ELISA for cytokines) were determined in cells exposed to C. trachomatis antigen. T-test was used to assess statistical significance (p<0.05). C. trachomatis antigen significantly induced expression of TLR4 (p=0.03) and activation of TAB1 (p=0.02) compared to controls. However, it did not induce p38 MAPK activation. In addition, pDECs maintained their stromal cell morphology when exposed to C. trachomatis antigen showing no signs of apoptosis and/or necrosis but did induce pro-inflammatory cytokine interleukin (IL)-6 (100ng/ml: p=0.02 and 200ng/ml: p=0.03), in pDECs compared to controls. Prenatal C. trachomatis infection can produce antigens that induce TLR4-TAB1 signaling and IL-6 inflammation independent of Pp38 MAPK and apoptosis and necrosis. This suggests that C. trachomatis can imbalance decidual inflammatory homeostasis, potentially contributing to adverse events during pregnancy.

Follistatin is a crucial chemoattractant for mouse decidualized endometrial stromal cell migration by JNK signalling

Follistatin (FST) and activin A as gonadal proteins exhibit opposite effects on follicle-stimulating hormone (FSH) release from pituitary gland, and activin A-FST system is involved in regulation of decidualization in reproductive biology. However, the roles of FST and activin A in migration of decidualized endometrial stromal cells are not well characterized. In this study, transwell chambers and microfluidic devices were used to assess the effects of FST and activin A on migration of decidualized mouse endometrial stromal cells (d-MESCs). We found that compared with activin A, FST exerted more significant effects on adhesion, wound healing and migration of d-MESCs. Similar results were also seen in the primary cultured decidual stromal cells (DSCs) from uterus of pregnant mouse. Simultaneously, the results revealed that FST increased calcium influx and upregulated the expression levels of the migration-related proteins MMP9 and Ezrin in d-MESCs. In addition, FST increased the level of phosphorylation of JNK in d-MESCs, and JNK inhibitor AS601245 significantly attenuated FST action on inducing migration of d-MESCs. These data suggest that FST, not activin A in activin A-FST system, is a crucial chemoattractant for migration of d-MESCs by JNK signalling to facilitate the successful uterine decidualization and tissue remodelling during pregnancy.

Decreased B7-H3 promotes unexplained recurrent miscarriage via RhoA/ROCK2 signaling pathway and regulates the secretion of decidual NK cells†.

The cause for at least 50% of recurrent miscarriages is unclear, which is defined as unexplained recurrent miscarriages. The B7-H1 (PD-L1), a molecule of the B7 family, promotes tumor development by modulating immune evasion, and recent researchers have also attached importance to the role of B7-H3, another molecule of B7 family, in tumor. Based on the similarity between growth and immune response in tumors and pregnancy, we first explored the role of B7-H3 in unexplained recurrent miscarriages. We found reduced levels of B7-H3 in the villus tissue of unexplained recurrent miscarriage patients, and it was mainly expressed on the cell membrane of extravillous trophoblasts. Further, the HTR-8/SVneo and JEG-3 cells were selected to explore the role of B7-H3 in proliferation, apoptosis, tube formation, migration, and invasion. We found that B7-H3 regulated trophoblast migration and invasion via RhoA/ROCK2 signaling pathway. Inflammatory cytokines were detected through enzyme-linked immunosorbent assay after co-culturing with decidual natural killer cells and B7-H3-knockout JEG-3. Results showed that B7-H3 inhibited IL-8 and IP-10 secretion from the decidual natural killer cells. In a CBA/J × DBA/2 abortion-prone mice model, treatment with B7-H3-Fc protein successfully reduced the rate of embryo resorption. In conclusion, our results revealed a possible mechanism by which decreased B7-H3 on trophoblasts of unexplained recurrent miscarriages inhibited trophoblast migration and invasion and increased IL-8 and IP-10 secretion from the decidual natural killer cells. Furthermore, B7-H3 may be a promising new therapeutic target in unexplained recurrent miscarriage patients.

Decidual natural killer cells and trophoblast cells: cellular, humoral and molecular mechanisms of interaction

Natural killer cells (NK cells) represent a group of lymphocytes of innate immunity. In addition to NK cells of peripheral blood, tissue-resident populations are described. NK cells of the decidual envelope (decidual NK cells) represent one of the local NK cell populations. Decidual NK cells differ in phenotype and function from peripheral blood NK cells. These cells have, mainly, regulatory functions. At the same time they retain the ability to perform cytotoxic effects. In the uterus, NK cells are located closely to the cells of fetal origin, i.e., trophoblast cells, which differentiate from the outer layer of the invading blastocyst. The purpose of the review article was to analyze the literature data on the studies of the molecular interactions between NK cells and trophoblast cells, as well as potential means of regulating these interactions. The review presents currently available data on receptor-mediated effects (due to adhesion molecules and cytotoxic receptors) and distant interactions (involving cytokines, chemokines and growth factors secreted by the both cell types) between NK population and trophoblast cells. The receptors regulating contacts of NK cells and trophoblast cells with extracellular matrix are also considered. The review provides information on activation of signaling pathways in NK cells and trophoblast cells resulting from their interaction with each other and components of the extracellular matrix. Currently, the molecular mechanisms regulating the NK cell functions and their interaction with trophoblast cells have not been studied sufficiently. The authors attempted to consider molecular regulation of the functional activity of NK cells mediated by the molecular complex of RNA polymerase II. We also describe participation of cyclin-dependent CDK8/19 kinases which comprise a part of the mediator complex which provides functioning of immune cells. The data on the participation of CDK8/19 in regulation of intracellular signaling pathways, as well as influence of CDK8/19 on the NK cell functions, are considered. Summarizing the data presented in the literature, one may emphasize that there is an extensive mutual influence of NK cells and trophoblast cells in decidual lining of uterus during pregnancy, thus leading to a changes in phenotype and functions of these cells. Experimental studies are required on the contribution of molecular mechanisms involved in transcription and translation processes to the biology of NK cells, and their role in maintaining interactions between NK cells and trophoblast cells, including the pathways involving CDK8/19.

An IGF1-expressing endometrial stromal cell population is associated with human decidualization

Decidualization refers to the process of transformation of endometrial stromal fibroblast cells into specialized decidual stromal cells that provide a nutritive and immunoprivileged matrix essential for blastocyst implantation and placental development. Deficiencies in decidualization are associated with a variety of pregnancy disorders, including female infertility, recurrent implantation failure (RIF), and miscarriages. Despite the increasing number of genes reportedly associated with endometrial receptivity and decidualization, the cellular and molecular mechanisms triggering and underlying decidualization remain largely unknown. Here, we analyze single-cell transcriptional profiles of endometrial cells during the window of implantation and decidual cells of early pregnancy, to gains insights on the process of decidualization. We observed a unique IGF1+ stromal cell that may initiate decidualization by single-cell RNA sequencing. We found the IL1B+ stromal cells promote gland degeneration and decidua hemostasis. We defined a subset of NK cells for accelerating decidualization and extravillous trophoblast (EVT) invasion by AREG-IGF1 and AREG-CSF1 regulatory axe. Further analysis indicates that EVT promote decidualization possibly by multiply pathways. Additionally, a systematic repository of cell-cell communication for decidualization was developed. An aberrant ratio conversion of IGF1+ stromal cells to IGF1R+ stromal cells is observed in unexplained RIF patients. Overall, a unique subpopulation of IGF1+ stromal cell is involved in initiating decidualization. Our observations provide deeper insights into the molecular and cellular characterizations of decidualization, and a platform for further development of evaluation of decidualization degree and treatment for decidualization disorder-related diseases.

Dysfunction of CCR1+ decidual macrophages is a potential risk factor in the occurrence of unexplained recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) puzzles 1-3% of women of childbearing age worldwide. Immunological factors account for more than 60% of cases of unexplained RPL (URPL); however, the underlying mechanism remains unclear. Here, using single-cell sequencing data and functional experiments with clinical samples, we identified a distinct population of CCR1+ decidual macrophages (dMφ) that were preferentially enriched in the decidua from normal early pregnancies but were substantially decreased in patients with URPL. Specific gene signatures endowed CCR1+ dMφ with immunosuppressive and migration-regulatory properties, which were attenuated in URPL. Additionally, CCR1+ dMφ promoted epithelial-to-mesenchymal transition (EMT) to promote trophoblast migration and invasion by activating the ERK1/2 signaling pathway. Decidual stromal cell (DSC)-derived CCL8 was the key regulator of CCR1+ dMφ as CCL8 recruited peripheral CCR1+ monocytes, induced a CCR1+ dMφ-like phenotype, and reinforced the CCR1+ dMφ-exerted modulation of trophoblasts. In patients with URPL, CCL8 expression in DSCs was decreased and trophoblast EMT was defective. Our findings revealed that CCR1+ dMφ play an important role in immune tolerance and trophoblast functions at the maternal-fetal interface. Additionally, decreased quantity and dysregulated function of CCR1+ dMφ result in URPL. In conclusion, we provide insights into the crosstalk between CCR1+ dMφ, trophoblasts, and DSCs at the maternal-fetal interface and macrophage-targeted interventions of URPL.