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Nature Communications Nov 2023Tissue-resident Natural Killer (trNK) cells are crucial components of local immunity that activate rapidly upon infection. However, under steady state conditions, their...
Tissue-resident Natural Killer (trNK) cells are crucial components of local immunity that activate rapidly upon infection. However, under steady state conditions, their responses are tightly controlled to prevent unwanted tissue damage. The mechanisms governing their differentiation and activation are not fully understood. Here, we characterise uterine trNK cells longitudinally during pregnancy by single cell RNA sequencing and find that the combined expression pattern of 4-1BB and CD55 defines their three distinct stages of differentiation in mice. Mechanistically, an IL-21R-STAT3 axis is essential for initiating the trNK cell differentiation. The fully differentiated trNK cells demonstrate enhanced functionality, which is necessary for remodelling spiral arteries in the decidua. We identify an apoptotic program that is specific to the terminal differentiation stage, which may preclude tissue damage by these highly activated trNK cells. In summary, uterine trNK cells become intensely active and effective during pregnancy, but tightly controlled via a differentiation program that also limits potential harm, suggesting an intricate mechanism for harnessing trNK cells in maintaining pregnancy.
Topics: Animals; Female; Mice; Pregnancy; Cell Differentiation; Killer Cells, Natural; Transcription Factors; Uterus; Receptors, Interleukin-21; STAT3 Transcription Factor; Signal Transduction
PubMed: 37925507
DOI: 10.1038/s41467-023-42990-0 -
Placenta Sep 2023Spiral artery remodeling is the process by which the uterine vessels become large bore low resistance conduits, allowing delivery of high volumes of maternal blood to... (Review)
Review
Spiral artery remodeling is the process by which the uterine vessels become large bore low resistance conduits, allowing delivery of high volumes of maternal blood to the placenta to nourish the developing fetus. Failure of this process is associated with the pathophysiology of most of the major obstetric complications, including late miscarriage, fetal growth restriction and pre-eclampsia. However, the point at which remodeling 'fails' in these pathological pregnancies is not yet clear. Spiral artery remodeling has predominantly been described in terms of its morphological features, however we are starting to understand more about the cellular and molecular triggers of the different aspects of this process. This review will discuss the current state of knowledge of spiral artery remodeling, in particular the processes involved in loss of the vascular smooth muscle cells, and consider where in the process defects would lead to a pathological pregnancy.
Topics: Pregnancy; Female; Humans; Trophoblasts; Placenta; Uterus; Arteries; Abortion, Spontaneous; Pre-Eclampsia; Vascular Remodeling; Decidua
PubMed: 37308346
DOI: 10.1016/j.placenta.2023.05.013 -
Medicine International 2024Subchorionic hematoma (SCH) is a hematoma in which blood accumulates between the chorion and decidua basalis due to the separation of the chorion and decidua basalis. It... (Review)
Review
Subchorionic hematoma (SCH) is a hematoma in which blood accumulates between the chorion and decidua basalis due to the separation of the chorion and decidua basalis. It is common in patients with threatened abortion in early pregnancy and is mainly detected by ultrasound. SCH mainly manifests as an hypoechoic or anechoic crescent-shaped fluid dark area on ultrasound images. Although there are numerous studies on SCH, its pathogenesis and etiology remain unclear, and its influence on pregnancy outcomes is also controversial; there are also no uniform clinical treatment guidelines. Current studies suggest that the occurrence of SCH may be related to several factors, such as abnormal coagulation function, autoimmune factors of pregnant women, assisted reproduction, drug use during pregnancy and reproductive tract infection; however, its exact etiology remains unclear. Some studies suggest that SCH is associated with adverse pregnancy outcomes such as miscarriage, preterm birth, preeclampsia and fetal growth restriction, although other studies have found that SCH does not increase the risk of adverse pregnancy outcomes. Therefore, the present review mainly discusses the pathogenesis, etiology and treatment of SCH in an aim to provide a reference for the clinical treatment of this condition in pregnant women.
PubMed: 38362561
DOI: 10.3892/mi.2024.134 -
Cureus Jun 2024Pregnancy is a highly regulated biological phenomenon that involves the development of a semi-allogeneic fetus inside the uterus of the mother. The maternal-fetal... (Review)
Review
Pregnancy is a highly regulated biological phenomenon that involves the development of a semi-allogeneic fetus inside the uterus of the mother. The maternal-fetal interface is a critical junction where communication takes place between the fetal and maternal immune systems, which determine the outcome of the pregnancy. The interface is composed of the decidua and placenta. The main cells present at the maternal-fetal interface include invading trophoblasts, maternal immune cells, and decidual stromal cells. Although maternal tolerance is crucial for maintaining a successful pregnancy, the role of the placenta in pregnancy is also important. Dysregulation of the placenta leads to various placenta-mediated complications, such as preeclampsia, intrauterine growth restriction, and placental abruption. Although the exact mechanism involving these complications is unclear, research has elucidated various factors involved in these pregnancy disorders. This review aimed to provide a summary of the maternal-fetal interface and immune mechanisms involved in placenta-mediated complications.
PubMed: 38882223
DOI: 10.7759/cureus.62457 -
Redox Biology Nov 2023Myeloperoxidase (MPO) is one of the most abundant proteins in neutrophil granules. It catalyzes the production of reactive oxygen species, which are important in...
Myeloperoxidase (MPO) is one of the most abundant proteins in neutrophil granules. It catalyzes the production of reactive oxygen species, which are important in inflammation and immune defense. MPO also binds to several proteins, lipids, and DNA to alter their function. MPO is present at the feto-maternal interface during pregnancy, where neutrophils are abundant. In this study, we determined the effect of MPO on JEG-3 human choriocarcinoma cells as a model of extravillous trophoblasts (EVTs) during early pregnancy. We found that MPO was internalized by JEG-3 cells and localized to the cytoplasm and nuclei. MPO internalization and activity enhanced JEG-3 cell migration and invasion, whereas this effect was impaired by pre-treating cells with heparin, to block cellular uptake, and MPO-activity inhibitor 4-ABAH. This study identifies a novel mechanism for the effect of MPO on EVT function during normal pregnancy and suggests a potential role of MPO in abnormal pregnancies.
Topics: Female; Humans; Pregnancy; Cell Line, Tumor; Choriocarcinoma; Peroxidase; Proteins; Trophoblasts
PubMed: 37776707
DOI: 10.1016/j.redox.2023.102885 -
Cell Reports Jul 2023Leukocyte diversity of the first-trimester maternal-fetal interface has been extensively described; however, the immunological landscape of the term decidua remains...
Leukocyte diversity of the first-trimester maternal-fetal interface has been extensively described; however, the immunological landscape of the term decidua remains poorly understood. We therefore profiled human leukocytes from term decidua collected via scheduled cesarean delivery. Relative to the first trimester, our analyses show a shift from NK cells and macrophages to T cells and enhanced immune activation. Although circulating and decidual T cells are phenotypically distinct, they demonstrate significant clonotype sharing. We also report significant diversity within decidual macrophages, the frequency of which positively correlates with pregravid maternal body mass index. Interestingly, the ability of decidual macrophages to respond to bacterial ligands is reduced with pregravid obesity, suggestive of skewing toward immunoregulation as a possible mechanism to safeguard the fetus against excessive maternal inflammation. These findings are a resource for future studies investigating pathological conditions that compromise fetal health and reproductive success.
Topics: Pregnancy; Female; Humans; Decidua; T-Lymphocytes; Reproduction; Killer Cells, Natural; Macrophages
PubMed: 37432849
DOI: 10.1016/j.celrep.2023.112769 -
Biology of Reproduction Dec 2023Infertility is a challenging health problem that affects 8-15% of couples worldwide. Establishing pregnancy requires successful embryo implantation, but about 85% of... (Review)
Review
Infertility is a challenging health problem that affects 8-15% of couples worldwide. Establishing pregnancy requires successful embryo implantation, but about 85% of unsuccessful pregnancies are due to embryo implantation failure or loss soon after. Factors crucial for successful implantation include invasive blastocysts, receptive endometrium, invasion of trophoblast cells, and regulation of immune tolerance at the maternal-fetal interface. Maternal-fetal crosstalk, which relies heavily on protein-protein interactions, is a critical factor in implantation that involves multiple cellular communication and molecular pathways. Glycosylation, a protein modification process, is closely related to cell growth, adhesion, transport, signal transduction, and recognition. Protein glycosylation plays a crucial role in maternal-fetal crosstalk and can be divided into N-glycosylation and O-glycosylation, which are often terminated by sialylation or fucosylation. This review article examines the role of protein glycosylation in maternal-fetal crosstalk based on two transcriptome datasets from the GEO database (GSE139087 and GSE113790) and existing research, particularly in the context of the mechanism of protein glycosylation and embryo implantation. Dysregulation of protein glycosylation can lead to adverse pregnancy outcomes, such as missed abortion and recurrent spontaneous abortion, underscoring the importance of a thorough understanding of protein glycosylation in the diagnosis and treatment of female reproductive disorders. This knowledge could have significant clinical implications, leading to the development of more effective diagnostic and therapeutic approaches for these conditions.
Topics: Pregnancy; Female; Humans; Glycosylation; Embryo Implantation; Endometrium; Pregnancy Outcome; Abortion, Habitual
PubMed: 37658761
DOI: 10.1093/biolre/ioad105 -
Frontiers in Immunology 2023
Topics: Pregnancy; Female; Humans; Abortion, Habitual; Decidua
PubMed: 38022573
DOI: 10.3389/fimmu.2023.1330701 -
Frontiers in Immunology 2023Preeclampsia is a pregnancy-specific disorder that always causes maternal and fetal serious adverse outcome. Disturbances in maternal immune tolerance to embryo at the...
BACKGROUND
Preeclampsia is a pregnancy-specific disorder that always causes maternal and fetal serious adverse outcome. Disturbances in maternal immune tolerance to embryo at the maternal-fetal interface (MFI) may be associated with preeclampsia onset. Recent studies have revealed the reduced expression pattern of HLA-F at the MFI in preeclampsia, while the mechanism of it mediating maternal fetal immune tolerance has not been revealed.
METHODS
Single-cell RNA sequencing on placental decidua was performed to reveal the immune disturbances landscape at the MFI in preeclampsia. Human Jar cells and NK-92MI cells were employed to study the role of HLA-F in trophoblasts and lymphocyte.
RESULTS
A total of 101,250 cells were classified into 22 cell clusters. Disease-related IGFBP1+SPP1+ extracellular villus trophoblast (EVT) was identified in the preeclamptic placental decidua, accompanied by newly discovered immune cellular dysfunction such as reduced ribosomal functions of NK populations and abnormal expression of antigen-presenting molecules in most cell clusters. Certain genes that are characteristic of the intermediate stage of myeloid or EVT cell differentiation were found to have unexplored but important functions in the pathogenesis of preeclampsia; specifically, we detected enhanced cell cross-talk between IGFBP1+SPP1+ EVT2 or SPP1+M1 cells and their receptor cell populations at the MFI of PE patients compared to controls. With respect to HLA-F, mIF staining confirmed its reduced expression in PE samples compared to controls. Over-expression of HLA-F in Jar cells promoted cell proliferation, invasion, and migration while under-expression had the opposite effect. In NK-92MI cells, over-expression of HLA-F increased the secretion of immunoregulation cytokines such as CSF1 and CCL22, and promoted adaptive NKG2C+NK cell transformation.
CONCLUSIONS
We revealed the immune disturbance landscape at the MFI in preeclampsia. Our findings regarding cellular heterogeneity and immune cellular dysfunction, as revealed by scRNA-seq, and the function of HLA-F in cells provide new perspectives for further investigation of their roles in the pathogenesis of preeclampsia, and then provide potential new therapeutic target.
Topics: Female; Humans; Pregnancy; Decidua; Immune Tolerance; Killer Cells, Natural; Placenta; Pre-Eclampsia
PubMed: 37854606
DOI: 10.3389/fimmu.2023.1234577 -
Frontiers in Immunology 2023Graft versus host disease (GVHD) can occur at any period post allogeneic hematopoietic stem cell transplantation as a common clinical complication contributing to... (Review)
Review
Graft versus host disease (GVHD) can occur at any period post allogeneic hematopoietic stem cell transplantation as a common clinical complication contributing to significant morbidity and mortality. Acute GVHD develops in approximately 30-50% of patients receiving transplants from matched related donors. High doses of steroids are used as first-line treatment, but are unsuccessful in around 40% of patients, resulting in the diagnosis of steroid-refractory acute GVHD. Consensus has yet to develop for the management of steroid-refractory acute GVHD, and prognosis at six months has been estimated at around 50%. Thus, it is critical to find effective treatments that increase survival of steroid-refractory acute GVHD. This article describes the currently known characteristics, pathophysiology, and treatments for GVHD, with a special focus on recent advances in cell therapies. In particular, a novel cell therapy using decidua stromal cells (DSCs) was recently shown to have promising results for acute GVHD, with improved effectiveness over previous treatments including mesenchymal stromal cells. At the Karolinska Institute, severe acute GVHD patients treated with placenta-derived DSCs supplemented with either 5% albumin or 10% AB plasma displayed a one-year survival rate of 76% and 47% respectively. Furthermore, patients with steroid-refractory acute GVHD, displayed survival rates of 73% with albumin and 31% with AB plasma-supplemented DSCs, compared to the 20% survival rate in the mesenchymal stromal cell control group. Adverse events and deaths were found to be attributed only to complications of hematopoietic stem cell transplant and GVHD, not to the study intervention. ASC Therapeutics, Inc, in collaboration with the Karolinska Institute, will soon initiate a phase 2 multicenter, open-label study to further assess the efficacy and safety of intravenous DSC treatment in sixty patients with Grade II-IV steroid-refractory acute GVHD. This novel cell therapy represents a promising treatment to combat the poor prognosis that steroid-refractory acute GVHD patients currently face.
Topics: Female; Humans; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Mesenchymal Stem Cell Transplantation; Steroids; Albumins; Multicenter Studies as Topic
PubMed: 37868964
DOI: 10.3389/fimmu.2023.1241068