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Human Reproduction (Oxford, England) Jan 2023Do distinct subpopulations of decidual stromal cells (DSCs) exist and if so, are given subpopulations enriched in recurrent miscarriage (RM)?
STUDY QUESTION
Do distinct subpopulations of decidual stromal cells (DSCs) exist and if so, are given subpopulations enriched in recurrent miscarriage (RM)?
SUMMARY ANSWER
Three subpopulations of DSCs were identified from which inflammatory DSCs (iDSCs) and glycolytic DSCs (glyDSCs) are significantly enriched in RM, with implicated roles in driving decidual inflammation and immune dysregulation.
WHAT IS KNOWN ALREADY
DSCs play crucial roles in establishing and maintaining a successful pregnancy; dysfunction of DSCs has been considered as one of the key reasons for the development of RM.
STUDY DESIGN, SIZE, DURATION
We collected 15 early decidual samples from five healthy donors (HDs) and ten RM patients to perform single-cell RNA sequencing (scRNA-seq). A total of 43 RM patients and 37 HDs were enrolled in the validation cohort.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Non-immune cells and immune cells of decidual tissues were sorted by flow cytometry to perform scRNA-seq. We used tissue microarrays (TMA) to validate three distinct subpopulations of DSCs. The expression of inflammatory and glycolytic proteins by DSCs was validated by immunohistochemistry (IHC) and multiplex immunohistochemistry (mIHC). Different subsets of decidual NK (dNK) cells and macrophages were also validated by multicolor flow cytometry and mIHC. Cell ligand-receptor and spatial analyses between DSCs and immune cells were analyzed by mIHC.
MAIN RESULTS AND THE ROLE OF CHANCE
We classify the DSCs into three subtypes based on scRNA-seq data: myofibroblastic (myDSCs), inflammatory (iDSCs) and glycolytic (glyDSCs), with the latter two being significantly enriched in RM patients. The distribution patterns of DSC subtypes in the RM and HD groups were validated by mIHC. Single-cell analyses indicate that the differentiation of iDSCs and glyDSCs may be coupled with the degrees of hypoxia. Consequently, we propose a pathological model in which a vicious circle is formed and fueled by hypoxic stress, uncontrolled inflammation and aberrant glycolysis. Furthermore, our results show that the inflammatory SPP1+ macrophages and CD18+ dNK cells are preferentially increased in the decidua of RM patients. Cell ligand-receptor and mIHC spatial analyses uncovered close interactions between pathogenic DSCs and inflammatory SPP1+ macrophages and CD18+ NK cells in RM patients.
LARGE SCALE DATA
The raw single-cell sequence data reported in this paper were deposited at the National Omics Data Encyclopedia (www.biosino.org), under the accession number OEP002901.
LIMITATIONS, REASONS FOR CAUTION
The number of decidual samples for scRNA-seq was limited and in-depth functional studies on DSCs are warranted in future studies.
WIDER IMPLICATIONS OF THE FINDINGS
Identification of three DSC subpopulations opens new avenues for further investigation of their roles in RM patients.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the Strategic Priority Research Program (No. XDB29030302), Frontier Science Key Research Project (QYZDB-SSW-SMC036), Chinese Academy of Sciences; National Key Research and Development Program of China (2021YFE0200600), National Natural Science Foundation of China (No. 31770960), Shanghai Municipal Science and Technology Major Project (No. 2019SHZDZX02, HS2021SHZX001), and Shanghai Committee of Science and Technology (17411967800). All authors report no conflict of interest.
Topics: Pregnancy; Female; Humans; Ligands; Decidua; China; Abortion, Habitual; Killer Cells, Natural; Stromal Cells
PubMed: 36355621
DOI: 10.1093/humrep/deac240 -
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 -
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 -
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 -
Trends in Molecular Medicine Jan 2017Physiologically, a successful pregnancy requires the maternal immune system to recognize and tolerate the semiallogeneic fetus, and allow for normal invasion of... (Review)
Review
Physiologically, a successful pregnancy requires the maternal immune system to recognize and tolerate the semiallogeneic fetus, and allow for normal invasion of trophoblasts. Thus, pregnancy complications are considered to be associated with dysfunctional maternal-fetal crosstalk. Co-signaling molecules are a group of cell surface molecules that positively or negatively modulate the immune response. Well studied in the fields of oncology and transplantation, they are also suggested to be involved in maternal-fetal crosstalk. Here, we review the latest knowledge on the expression and function of such co-signaling molecules, highlighting their immunoregulatory roles in maternal-fetal tolerance and decidual vascular remodeling, and their involvement in pathological pregnancies. This review may instruct future basic research on, and clinical applications for, maternal-fetal immunity.
Topics: Animals; Decidua; Female; Fetus; Humans; Immune Tolerance; Immunity; Maternal-Fetal Exchange; Mice; Pregnancy; Pregnancy Complications; Signal Transduction; Trophoblasts
PubMed: 27914866
DOI: 10.1016/j.molmed.2016.11.001 -
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 -
Molecular Reproduction and Development Aug 2020Decidualization is a crucial precedent to embryo implantation, as its impairment is a major contributor to female infertility and pregnancy complications. Unraveling the... (Review)
Review
Decidualization is a crucial precedent to embryo implantation, as its impairment is a major contributor to female infertility and pregnancy complications. Unraveling the molecular mechanisms involved in the impairment of decidualization has been a subject of interest in the field of reproductive medicine. Evidence from several experimental settings show that exposure to bisphenol A (BPA), an endocrine-disrupting chemical, affects the expression of several molecules that are involved in decidualization. Both low and high doses of BPA impair decidualization through the dysregulation of estrogen (ER) and progesterone (PR) receptors. Exposure to low doses of BPA leads to decreased levels and activities of several antioxidant enzymes, increased activity of endothelial nitric oxide synthase (eNOS), and increased production of nitric oxide (NO) via the upregulation of ER and PR. Consequently, oxidative stress is induced and decidualization becomes impaired. On the other hand, exposure to high doses of BPA downregulates ER and PR and impairs decidualization through two distinct pathways. One is through the upregulation of early growth response-1 (EGR1) via increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2; and the other is through a reduced serum glucocorticoid-induced kinase-1 (SGK1)-mediated downregulation of epithelial sodium channel-α and the induction of oxidative stress. Thus, regardless of the dose, BPA can impair decidualization to trigger infertility and pregnancy complications. This warrants the need to adopt lifestyles that will decrease the tendency of getting exposed to BPA.
Topics: Animals; Benzhydryl Compounds; Decidua; Embryo Implantation; Embryo Implantation, Delayed; Endocrine Disruptors; Female; Humans; Phenols; Placenta Diseases; Pregnancy; Signal Transduction
PubMed: 32691498
DOI: 10.1002/mrd.23400