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Frontiers in Immunology 2023Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality. Although increasing lines of evidence suggest that both the placenta and the decidua...
Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality. Although increasing lines of evidence suggest that both the placenta and the decidua likely play roles in the pathogenesis of PE, the molecular mechanism of PE remains elusive partly because of the heterogeneity nature of the maternal-fetal interface. In this study, we perform single-cell RNA-seq on the placenta and the decidual from patients with late-onset PE (LOPE) and women in normal pregnancy. Analyses of single-cell transcriptomes reveal that in LOPE, there are likely a global development deficiency of trophoblasts with impaired invasion of extravillous trophoblasts (EVT) and increased maternal immune rejection and inflammation in the placenta, while there are likely insufficient decidualization of decidual stromal cells (DSC), increased inflammation, and suppressed regulatory functions of decidual immune cells. These findings improve our understanding of the molecular mechanisms of PE.
Topics: Pregnancy; Humans; Female; Placentation; Pre-Eclampsia; Single-Cell Gene Expression Analysis; Decidua; Inflammation
PubMed: 37283740
DOI: 10.3389/fimmu.2023.1142273 -
Human Reproduction Update Apr 2021Endometrium is a vital multicellular tissue for progression of pregnancy. Forkhead box O1 (FoxO1) transcription factor plays an important role in the endometrium as it... (Review)
Review
BACKGROUND
Endometrium is a vital multicellular tissue for progression of pregnancy. Forkhead box O1 (FoxO1) transcription factor plays an important role in the endometrium as it regulates various cellular processes with its unique expression in different cell types.
OBJECTIVE AND RATIONALE
This review focuses on the role of FoxO1 in endometrium with a particular emphasis on FoxO1 signaling in individual endometrial cell types during the menstrual cycle and early pregnancy.
SEARCH METHODS
A literature search was conducted in PubMed, Web of Science and Scopus to select studies reporting the role of FoxO1 in endometrium using the keywords: FoxO1, endometrium, menstrual cycle, early pregnancy, endometrial receptivity, implantation, decidualization, angiogenesis and neoplasia. Papers published before October 2020 were selected. Drawing on advances in laboratory science and preclinical studies, we performed a narrative review of the scientific literature to provide a timely update on the roles of FoxO1 during the menstrual cycle and early pregnancy.
OUTCOMES
FoxO1 is considered to be a decidualization marker in endometrial stromal cells, mainly because it regulates the transcription of decidual prolactin and insulin-like growth factor-binding protein 1 genes. Importantly, 507 of 3405 genes that are specifically regulated during decidualization of human endometrial stromal cells are expressed abnormally as a result of FOXO1 reduction. Epithelial FoxO1 is currently accepted as a novel endometrial receptivity marker for humans and mice owing to its timely and specific expression at the window of implantation. On the other hand, FOXO1 is essential in endometrial epithelial cell proliferation and differentiation to achieve endometrial homeostasis since loss of function of FOXO1 causes endometrial neoplasia. Last but not least, FoxO1 seems to act like a navigator molecule for embryo homing owing to its notably decreased nuclear expression in endometrial luminal epithelial cells, specifically at the blastocyst attachment region, which results in differentiation, entosis and apoptosis of endometrial epithelial cells during the peri-implantation period. In endothelium, FoxO1 expression coincides with the timing of increased vascular permeabilization during early pregnancy. There are limited data regarding the importance of FoxO1 upregulation in endometrial endothelial cells, therefore, it is time to investigate the role of endothelial FoxO1, which is the missing piece in the puzzle of the enigmatic endometrium. Another missing piece in the puzzle for the role of FoxO1 is on embryo development.
WIDER IMPLICATIONS
FoxO1 is a cell-specific core transcription factor involved in efficient endometrial remodeling during the menstrual cycle and early pregnancy. A better understanding of the role of FoxO1 as a decidualization marker, as an emerging marker of endometrial receptivity, and as a therapeutic target to prevent endometrial neoplasia could help us to make sense of endometrial biology and thus to improve the outcomes of ART in the clinic.
Topics: Animals; Decidua; Embryo Implantation; Endometrium; Endothelial Cells; Female; Forkhead Box Protein O1; Homeostasis; Humans; Menstrual Cycle; Mice; Pregnancy; Stromal Cells; Transcription Factors
PubMed: 33434267
DOI: 10.1093/humupd/dmaa060 -
Cell Reports. Medicine May 2023Recurrent spontaneous miscarriage (RSM) affects 1%-2% of fertile women worldwide and poses a risk of future pregnancy complications. Increasing evidence has indicated...
Recurrent spontaneous miscarriage (RSM) affects 1%-2% of fertile women worldwide and poses a risk of future pregnancy complications. Increasing evidence has indicated that defective endometrial stromal decidualization is a potential cause of RSM. Here, we perform liquid chromatography with mass spectrometry (LC-MS)-based metabolite profiling in human endometrial stromal cells (ESCs) and differentiated ESCs (DESCs) and find that accumulated α-ketoglutarate (αKG) derived from activated glutaminolysis contributes to maternal decidualization. Contrarily, ESCs obtained from patients with RSM show glutaminolysis blockade and aberrant decidualization. We further find that enhanced Gln-Glu-αKG flux decreases histone methylation and supports ATP production during decidualization. In vivo, feeding mice a Glu-free diet leads to a reduction of αKG, impaired decidualization, and an increase of fetal loss rate. Isotopic tracing approaches demonstrate Gln-dependent oxidative metabolism as a prevalent direction during decidualization. Our results demonstrate an essential prerequisite of Gln-Glu-αKG flux to regulate maternal decidualization, suggesting αKG supplementation as a putative strategy to rectify deficient decidualization in patients with RSM.
Topics: Pregnancy; Humans; Female; Mice; Animals; Decidua; Ketoglutaric Acids; Abortion, Spontaneous; Cells, Cultured; Endometrium
PubMed: 37137303
DOI: 10.1016/j.xcrm.2023.101026 -
Proceedings of the National Academy of... Sep 2022In humans, the uterus undergoes a dramatic transformation to form an endometrial stroma-derived secretory tissue, termed decidua, during early pregnancy. The decidua...
In humans, the uterus undergoes a dramatic transformation to form an endometrial stroma-derived secretory tissue, termed decidua, during early pregnancy. The decidua secretes various factors that act in an autocrine/paracrine manner to promote stromal differentiation, facilitate maternal angiogenesis, and influence trophoblast differentiation and development, which are critical for the formation of a functional placenta. Here, we investigated the mechanisms by which decidual cells communicate with each other and with other cell types within the uterine milieu. We discovered that primary human endometrial stromal cells (HESCs) secrete extracellular vesicles (EVs) during decidualization and that this process is controlled by a conserved HIF2α-RAB27B pathway. Mass spectrometry revealed that the decidual EVs harbor a variety of protein cargo, including cell signaling molecules, growth modulators, metabolic regulators, and factors controlling endothelial cell expansion and remodeling. We tested the hypothesis that EVs secreted by the decidual cells mediate functional communications between various cell types within the uterus. We demonstrated that the internalization of EVs, specifically those carrying the glucose transporter 1 (GLUT1), promotes glucose uptake in recipient HESCs, supporting and advancing the decidualization program. Additionally, delivery of HESC-derived EVs into human endothelial cells stimulated their proliferation and led to enhanced vascular network formation. Strikingly, stromal EVs also promoted the differentiation of trophoblast stem cells into the extravillous trophoblast lineage. Collectively, these findings provide a deeper understanding of the pleiotropic roles played by EVs secreted by the decidual cells to ensure coordination of endometrial differentiation and angiogenesis with trophoblast function during the progressive phases of decidualization and placentation.
Topics: Cell Differentiation; Decidua; Endothelial Cells; Extracellular Vesicles; Female; Humans; Neovascularization, Physiologic; Pregnancy; Stromal Cells; Trophoblasts
PubMed: 36095212
DOI: 10.1073/pnas.2200252119 -
Nature Communications Feb 2022During decidualization in rodents, uterine stroma undergoes extensive reprograming into distinct cells, forming the discrete regions defined as the primary decidual zone...
During decidualization in rodents, uterine stroma undergoes extensive reprograming into distinct cells, forming the discrete regions defined as the primary decidual zone (PDZ), the secondary decidual zone (SDZ) and the layer of undifferentiated stromal cells respectively. Here we show that uterine deletion of Men1, a member of the histone H3K4 methyltransferase complex, disrupts the terminal differentiation of stroma, resulting in chaotic decidualization and pregnancy failure. Genome-wide epigenetic profile reveals that Men1 binding in chromatin recapitulates H3K4me3 distribution. Further transcriptomic investigation demonstrates that Men1 directly regulates the expression of PTX3, an extra-cellular trap for FGF2 in decidual cells. Decreased Ptx3 upon Men1 ablation leads to aberrant activation of ERK1/2 in the SDZ due to the unrestrained FGF2 signal emanated from undifferentiated stromal cells, which blunt BMP2 induction and decidualization. In brief, our study provides genetic and molecular mechanisms for epigenetic rewiring mediated decidual regionalization by Men1 and sheds new light on pregnancy maintenance.
Topics: C-Reactive Protein; Decidua; Embryo Implantation; Female; Fibroblast Growth Factor 2; Humans; Pregnancy; Serum Amyloid P-Component; Signal Transduction; Stromal Cells; Transcription Factors; Uterus
PubMed: 35194044
DOI: 10.1038/s41467-022-28657-2 -
Communications Biology Jan 2020During the implantation window, the endometrium becomes poised to transition to a pregnant state, a process driven by differentiation of stromal cells into decidual...
During the implantation window, the endometrium becomes poised to transition to a pregnant state, a process driven by differentiation of stromal cells into decidual cells (DC). Perturbations in this process, termed decidualization, leads to breakdown of the feto-maternal interface and miscarriage, but the underlying mechanisms are poorly understood. Here, we reconstructed the decidual pathway at single-cell level in vitro and demonstrate that stromal cells first mount an acute stress response before emerging as DC or senescent DC (snDC). In the absence of immune cell-mediated clearance of snDC, secondary senescence transforms DC into progesterone-resistant cells that abundantly express extracellular matrix remodelling factors. Additional single-cell analysis of midluteal endometrium identified DIO2 and SCARA5 as marker genes of a diverging decidual response in vivo. Finally, we report a conspicuous link between a pro-senescent decidual response in peri-implantation endometrium and recurrent pregnancy loss, suggesting that pre-pregnancy screening and intervention may reduce the burden of miscarriage.
Topics: Abortion, Habitual; Cell Line; Cellular Senescence; Decidua; Disease Susceptibility; Embryo Implantation; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Humans; Immunologic Surveillance; Models, Biological; Pregnancy; Signal Transduction; Single-Cell Analysis; Transcriptome
PubMed: 31965050
DOI: 10.1038/s42003-020-0763-1 -
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 -
Frontiers in Immunology 2023A successful human pregnancy requires the maternal immune system to recognize and tolerate the semi-allogeneic fetus, allowing for appropriate trophoblasts invasion and... (Review)
Review
A successful human pregnancy requires the maternal immune system to recognize and tolerate the semi-allogeneic fetus, allowing for appropriate trophoblasts invasion and protecting the fetus from invading pathogens. Therefore, maternal immunity is critical for the establishment and maintenance of pregnancy, especially at the maternal-fetal interface. Anatomically, the maternal-fetal interface has both maternally- and fetally- derived cells, including fetal originated trophoblasts and maternal derived immune cells and stromal cells. Besides, a commensal microbiota in the uterus was supposed to aid the unique immunity in pregnancy. The appropriate crosstalk between fetal derived and maternal originated cells and uterine microbiota are critical for normal pregnancy. Dysfunctional maternal-fetal interactions might be associated with the development of pregnancy complications. This review elaborates the latest knowledge on the interactions between trophoblasts and decidual immune cells, highlighting their critical roles in maternal-fetal tolerance and pregnancy development. We also characterize the role of commensal bacteria in promoting pregnancy progression. Furthermore, this review may provide new thought on future basic research and the development of clinical applications for pregnancy complications.
Topics: Pregnancy; Female; Humans; Decidua; Fetus; Uterus; Trophoblasts; Pregnancy Complications
PubMed: 37350956
DOI: 10.3389/fimmu.2023.1198430 -
Human Immunology May 2021Cytotrophoblasts differentiate in two directions during early placentation: syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). STBs face maternal immune... (Review)
Review
Cytotrophoblasts differentiate in two directions during early placentation: syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). STBs face maternal immune cells in placentas, and EVTs, which invade the decidua and uterine myometrium, face the cells in the uterus. This situation, in which trophoblasts come into contact with maternal immune cells, is known as the maternal-fetal interface. Despite fetuses and fetus-derived trophoblast cells being of the semi-allogeneic conceptus, fetuses and placentas are not rejected by the maternal immune system because of maternal-fetal tolerance. The acquired tolerance develops during normal placentation, resulting in normal fetal development in humans. In this review, we introduce placental development from the viewpoint of molecular biology. In addition, we discuss how the disruption of placental development could lead to complications in pregnancy, such as hypertensive disorder of pregnancy, fetal growth restriction, or miscarriage.
Topics: Animals; Autophagy; Decidua; Female; Giant Cells; Histocompatibility, Maternal-Fetal; Humans; Immune Tolerance; Placenta; Pregnancy; T-Lymphocytes, Regulatory
PubMed: 33581928
DOI: 10.1016/j.humimm.2021.01.012 -
Human Reproduction (Oxford, England) Jun 2022What are the consequences of endometrial stromal cell (EnSC) senescence for endometrial function?
STUDY QUESTION
What are the consequences of endometrial stromal cell (EnSC) senescence for endometrial function?
SUMMARY ANSWER
Senescence of EnSC contributes to impaired endometrial decidualization and impaired interaction with trophoblast cells but application of senomorphics diminishes the adverse effects of senescent EnSC on decidualization and implantation.
WHAT IS KNOWN ALREADY
A prolonged and highly disordered pro-inflammatory secretory profile of EnSC, which resembles the senescence-associated secretory phenotype, is associated with implantation failure. Furthermore, it has been suggested that implantation failure may be associated with increased EnSC senescence during the proliferative phase of the menstrual cycle.
STUDY DESIGN, SIZE, DURATION
Primary EnSC cell cultures were isolated from endometrial biopsies taken from four patients without any endometrial complications planning to undergo IVF. EnSC senescence was induced by oxidative stress (1 h exposure to 200 µM H2O2) followed by 14 days culture but some results were confirmed in a replicative senescence model (after 25 passages). The decidual reaction was evaluated with routine methods and a genetic tool previously designed by us that estimates integral decidual response by fluorescence of a reporter protein. Time-course RNA-sequencing of control and senescent EnSC before and during decidualization was performed using four replicates for each state. To extend our findings, we applied several publicly available datasets. To model implantation in vitro, the choriocarcinoma cell line BeWo b30 was used. To reduce the senescent phenotype of EnSC, two classical senomorphics were applied-rapamycin and metformin.
PARTICIPANTS/MATERIALS, SETTING, METHODS
EnSC cultures were used to investigate the effects of senescence on decidualization and on an in vitro implantation model using spheroids derived from BeWo cells. Co-culture models (2D and 3D) were used to explore the effect of senescent cells on neighbouring control cells. The following methods were used to assess cell function, RNA-sequencing, bioinformatic analysis, CRISPR/Cas9 genome editing, FACS, western blotting, RT-PCR, immunofluorescence, molecular cloning, lentiviral transduction and ELISA.
MAIN RESULTS AND THE ROLE OF CHANCE
Premature senescence of EnSC could be a cause of impaired decidualization. Hormone-induced decidual transformation of EnSC cultures was negatively affected by senescence. Bioinformatics revealed crucial disturbances in the decidual reaction of senescent EnSC which could affect embryo invasion, alter the 'meta-signature' of human endometrial receptivity, disturb the emergence of mature and senescent decidual cells subpopulations, impair ligand-receptor interaction with trophoblasts and modify the architecture of extracellular matrix. These predictions were functionally validated using an in vitro implantation model. Moreover, we observed that senescent EnSC, likely via the altered secretome, caused 'bystander' quenching of the decidual reaction in adjacent cells, reinforcing dysfunction of the stromal compartment. Application of senomorphics that reduced the senescence phenotype diminished adverse effects of senescent EnSC on decidualization and implantation.
LARGE SCALE DATA
The data used in this study are available in the GEO database (GEO identifier GSE160702).
LIMITATIONS, REASONS FOR CAUTION
The present study was based on in vitro cell cultures derived from only four women. Further studies involving patients with impaired implantation are needed to confirm our findings.
WIDER IMPLICATIONS OF THE FINDINGS
The presence of senescent EnSC within the stromal compartment of the endometrium may be a risk-factor for the failure of embryo implantation. Application of senomorphics during the proliferative phase of the menstrual cycle is a promising strategy to alleviate negative effects of senescent EnSC and to improve embryo implantation rates.
STUDY FUNDING/COMPETING INTEREST(S)
This study was funded by the Russian Science Foundation (# 19-74-10038). The authors do not have any competing interests to declare.
Topics: Cellular Senescence; Decidua; Embryo Implantation; Endometrium; Female; Humans; Hydrogen Peroxide; Pregnancy; RNA; Stromal Cells; Trophoblasts
PubMed: 35604371
DOI: 10.1093/humrep/deac112