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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 -
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 -
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 -
Proceedings of the National Academy of... Oct 2021Miscarriage is a common complication of pregnancy for which there are few clinical interventions. Deficiency in endometrial stromal cell decidualization is considered a...
Miscarriage is a common complication of pregnancy for which there are few clinical interventions. Deficiency in endometrial stromal cell decidualization is considered a major contributing factor to pregnancy loss; however, our understanding of the underlying mechanisms of decidual deficiency are incomplete. ADP ribosylation by PARP-1 and PARP-2 has been linked to physiological processes essential to successful pregnancy outcomes. Here, we report that the catalytic inhibition or genetic ablation of PARP-1 and PARP-2 in the uterus lead to pregnancy loss in mice. Notably, the absence of PARP-1 and PARP-2 resulted in increased p53 signaling and an increased population of senescent decidual cells. Molecular and histological analysis revealed that embryo attachment and the removal of the luminal epithelium are not altered in uterine , knockout mice, but subsequent decidualization failure results in pregnancy loss. These findings provide evidence for a previously unknown function of PARP-1 and PARP-2 in mediating decidualization for successful pregnancy establishment.
Topics: Abortion, Spontaneous; Animals; Decidua; Embryo Implantation; Embryo, Mammalian; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Pregnancy; Pregnancy Outcome; Signal Transduction; Stromal Cells; Uterus
PubMed: 34580230
DOI: 10.1073/pnas.2109252118 -
Frontiers in Physiology 2020The characteristics of fetal membrane cells and their phenotypic adaptations to support pregnancy or promote parturition are defined by global patterns of gene... (Review)
Review
The characteristics of fetal membrane cells and their phenotypic adaptations to support pregnancy or promote parturition are defined by global patterns of gene expression controlled by chromatin structure. Heritable epigenetic chromatin modifications that include DNA methylation and covalent histone modifications establish chromatin regions permissive or exclusive of regulatory interactions defining the cell-specific scope and potential of gene activity. Non-coding RNAs acting at the transcriptional and post-transcriptional levels complement the system by robustly stabilizing gene expression patterns and contributing to ordered phenotype transitions. Here we review currently available information about epigenetic gene regulation in the amnion and the chorion laeve. In addition, we provide an overview of epigenetic phenomena in the decidua, which is the maternal tissue fused to the chorion membrane forming the anatomical and functional unit called choriodecidua. The relationship of gene expression with DNA (CpG) methylation, histone acetylation and methylation, micro RNAs, long non-coding RNAs and chromatin accessibility is discussed in the context of normal pregnancy, parturition and pregnancy complications. Data generated using clinical samples and cell culture models strongly suggests that epigenetic events are associated with the phenotypic transitions of fetal membrane cells during the establishment, maintenance and termination of pregnancy potentially driving and consolidating the changes as pregnancy progresses. Disease conditions and environmental factors may produce epigenetic footprints that indicate exposures and mediate adverse pregnancy outcomes. Although knowledge is expanding rapidly, fetal membrane epigenetics is still in an early stage of development necessitating further research to realize its remarkable basic and translational potential.
PubMed: 33343389
DOI: 10.3389/fphys.2020.588539 -
Journal of Advanced Research May 2021Recurrent implantation failure (RIF) is a challenging problem of assisted reproductive technology that arises mainly due to inadequate endometrial receptivity and its...
INTRODUCTION
Recurrent implantation failure (RIF) is a challenging problem of assisted reproductive technology that arises mainly due to inadequate endometrial receptivity and its pathogenesis is still unclear.
OBJECTIVES
In this study, we conducted the first investigation of the effect of decreased PIBF1 expression in mid-secretory phase on endometrial receptivity in patients with RIF.
METHODS
Microarray assay, reverse transcriptase-quantitative polymerase chain reaction, western blot, and in-vitro experiments were conducted.
RESULTS
The results showed that progesterone-induced blocking factor 1 (PIBF1) expression was highest in the mid-secretory endometrium in control subjects, but was significantly lower in RIF patients. In Ishikawa and human endometrial stromal cells (HESCs), rather than human endometrial epithelial cells, PIBF1 knockdown significantly downregulated cell proliferation and the levels of interleukin 6 (IL6) and phosphorylated signal transducer and activator of transcription-3 (p-STAT3). Besides, in HESCs, the levels of IL6, p-STAT3, prolactin and insulin-like growth factor binding-protein-1 (IGFBP1) decreased after PIBF1 knockdown during in-vitro decidualization. All these cellular changes could be notably restored by PIBF1 or IL6 overexpression. Consistent with our findings with PIBF1, the levels of IL6, p-STAT3, ki-67, prolactin, and IGFBP1 in the mid-secretory endometrium were notably lower in patients with RIF compared with controls.
CONCLUSION
In summary, in the mid-secretory phase, decreased expression of PIBF1, IL6, and p-STAT3 inhibited HESC proliferation and decidualization, which is of theoretical and clinical importance for future research and clinical-treatment strategies.
Topics: Adult; Cell Proliferation; Decidua; Embryo Implantation; Endometrium; Epithelial Cells; Female; Humans; Insulin-Like Growth Factor Binding Protein 1; Interleukin-6; Pregnancy Proteins; Prolactin; Reproductive Techniques, Assisted; STAT3 Transcription Factor; Stromal Cells; Suppressor Factors, Immunologic
PubMed: 34026283
DOI: 10.1016/j.jare.2020.09.002 -
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