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Nature Nov 2018During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and...
During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblast-decidual interactions underlie common diseases of pregnancy, including pre-eclampsia and stillbirth. Here we profile the transcriptomes of about 70,000 single cells from first-trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals subsets of perivascular and stromal cells that are located in distinct decidual layers. There are three major subsets of decidual natural killer cells that have distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand-receptor complexes and a statistical tool to predict the cell-type specificity of cell-cell communication via these molecular interactions. Our data identify many regulatory interactions that prevent harmful innate or adaptive immune responses in this environment. Our single-cell atlas of the maternal-fetal interface reveals the cellular organization of the decidua and placenta, and the interactions that are critical for placentation and reproductive success.
Topics: Cell Communication; Cell Differentiation; Decidua; Female; Fetus; Histocompatibility, Maternal-Fetal; Humans; Killer Cells, Natural; Ligands; Placenta; Pregnancy; RNA, Small Cytoplasmic; Sequence Analysis, RNA; Single-Cell Analysis; Stromal Cells; Transcriptome; Trophoblasts
PubMed: 30429548
DOI: 10.1038/s41586-018-0698-6 -
Science Immunology Jan 2019Pregnancy poses an immunological challenge because a genetically distinct (nonself) fetus must be supported within the pregnant female for the required gestational... (Review)
Review
Pregnancy poses an immunological challenge because a genetically distinct (nonself) fetus must be supported within the pregnant female for the required gestational period. Placentation, or the establishment of the fetally derived placenta, is a common strategy used by eutherian mammals to protect the fetus and promote its growth. However, the substantial morphological differences of the placental architecture among species suggest that the process of placentation results from convergent evolution. Although there are considerable similarities in placental function across placental mammals, there are important differences that arise owing to species-specific immunological (and other biological) constraints. This Review focuses on the immunological similarities and differences that occur at the maternal-fetal interface in the context of human and mouse pregnancies. We discuss how the decidua and placenta of these different species form key immunological barriers that sustain maternal tolerance yet generate innate immune responses that prevent microbial infections.
Topics: Animals; Decidua; Female; Humans; Immune Tolerance; Infections; Leukocytes; Placenta; Pregnancy
PubMed: 30635356
DOI: 10.1126/sciimmunol.aat6114 -
Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium.Nature Cell Biology May 2017In humans, the endometrium, the uterine mucosal lining, undergoes dynamic changes throughout the menstrual cycle and pregnancy. Despite the importance of the endometrium...
In humans, the endometrium, the uterine mucosal lining, undergoes dynamic changes throughout the menstrual cycle and pregnancy. Despite the importance of the endometrium as the site of implantation and nutritional support for the conceptus, there are no long-term culture systems that recapitulate endometrial function in vitro. We adapted conditions used to establish human adult stem-cell-derived organoid cultures to generate three-dimensional cultures of normal and decidualized human endometrium. These organoids expand long-term, are genetically stable and differentiate following treatment with reproductive hormones. Single cells from both endometrium and decidua can generate a fully functional organoid. Transcript analysis confirmed great similarity between organoids and the primary tissue of origin. On exposure to pregnancy signals, endometrial organoids develop characteristics of early pregnancy. We also derived organoids from malignant endometrium, and so provide a foundation to study common diseases, such as endometriosis and endometrial cancer, as well as the physiology of early gestation.
Topics: Adult Stem Cells; Cell Culture Techniques; Cell Differentiation; Cell Lineage; Cell Proliferation; Cells, Cultured; Culture Media; Decidua; Endometrial Neoplasms; Endometrium; Estrogens; Female; Gene Expression Regulation, Developmental; Genotype; Humans; Organoids; Phenotype; Pregnancy; Progesterone; Time Factors; Tissue Engineering; Tumor Cells, Cultured
PubMed: 28394884
DOI: 10.1038/ncb3516 -
Best Practice & Research. Clinical... Jul 2018Historically, the evolutionary origins of menstruation have been based on two theories: the ability to eliminate infectious agents carried to the uterus with spermatozoa... (Review)
Review
Historically, the evolutionary origins of menstruation have been based on two theories: the ability to eliminate infectious agents carried to the uterus with spermatozoa and the comparative conservation of energy with menstruation compared to its absence. In the menstruating species, more recent theories have identified spontaneous decidualization as the key adaptive mechanism. Spontaneous decidualization is seen as a mechanism to provide the mother with protection from the invasive characteristics of the embryo. Physiologically, menstruation involves complex interactions of inflammation and vascular mechanisms to stabilize the endometrium and allow a regulated loss of endometrial tissues and blood. A variety of human illnesses can be better understood as vulnerabilities associated with these evolutionary developments, including recurrent pregnancy loss, placenta accreta, ectopic pregnancy, endometriosis, adenomyosis, dysmenorrhea, and chronic pelvic pain. While the evolutionary aspects of these diseases indicate why such illnesses can occur, in some instances, they also provide a basis for treatment, prevention and future research direction.
Topics: Animals; Biological Evolution; Decidua; Female; Humans; Menstruation
PubMed: 29530426
DOI: 10.1016/j.bpobgyn.2018.01.007 -
Cell Proliferation Nov 2021Successful pregnancy involves the homeostasis between maternal decidua and fetoplacental units, whose disruption contributes to compromised pregnancy outcomes, including...
OBJECTIVES
Successful pregnancy involves the homeostasis between maternal decidua and fetoplacental units, whose disruption contributes to compromised pregnancy outcomes, including recurrent spontaneous abortion (RSA). The role of cell heterogeneity of maternal decidua in RSA is yet to be illustrated.
MATERIALS AND METHODS
A total of 66,078 single cells from decidua samples isolated from patients with RSA and healthy controls were analysed by unbiased single-cell RNA sequencing (scRNA-seq).
RESULTS
Our scRNA-seq results revealed that stromal cells are the most abundant cell type in decidua during early pregnancy. RSA samples are accompanied by aberrant decidualization and obviously obstructed communication between stromal cells and other cell types, such as abnormal activation of macrophages and NK cells. In addition, the over-activated TNF superfamily member 12 (TNFSF12, TWEAK) and FASLG in RSA are closely related to stromal cell demise and pregnancy failure.
CONCLUSIONS
Our research reveals that the cell composition and communications in normal and RSA decidua at early pregnancy and provides insightful information for the pathology of RSA and will pave the way for pregnancy loss prevention.
Topics: Abortion, Habitual; Adult; Decidua; Female; Gene Expression Profiling; Humans; Killer Cells, Natural; Pregnancy; Single-Cell Analysis; Trophoblasts; Young Adult
PubMed: 34546587
DOI: 10.1111/cpr.13125 -
Nature Medicine Oct 2020In a human menstrual cycle the endometrium undergoes remodeling, shedding and regeneration, all of which are driven by substantial gene expression changes in the...
In a human menstrual cycle the endometrium undergoes remodeling, shedding and regeneration, all of which are driven by substantial gene expression changes in the underlying cellular hierarchy. Despite its importance in human fertility and regenerative biology, our understanding of this unique type of tissue homeostasis remains rudimentary. We characterized the transcriptomic transformation of human endometrium at single-cell resolution across the menstrual cycle, resolving cellular heterogeneity in multiple dimensions. We profiled the behavior of seven endometrial cell types, including a previously uncharacterized ciliated cell type, during four major phases of endometrial transformation, and found characteristic signatures for each cell type and phase. We discovered that the human window of implantation opens with an abrupt and discontinuous transcriptomic activation in the epithelia, accompanied with a widespread decidualization feature in the stromal fibroblasts. Our study provides a high-resolution molecular and cellular characterization of human endometrial transformation across the menstrual cycle, providing insights into this essential physiological process.
Topics: Adolescent; Adult; Atlases as Topic; Biopsy; Decidua; Embryo Implantation; Endometrium; Epithelium; Female; Gene Expression Profiling; Humans; Menstrual Cycle; Single-Cell Analysis; Stromal Cells; Transcriptome; Young Adult
PubMed: 32929266
DOI: 10.1038/s41591-020-1040-z -
Cell Reports Jan 2023During human pregnancy, placenta-derived extravillous trophoblasts (EVTs) invade the decidua and communicate with maternal immune cells. The decidua distinguishes into...
During human pregnancy, placenta-derived extravillous trophoblasts (EVTs) invade the decidua and communicate with maternal immune cells. The decidua distinguishes into basalis (decB) and parietalis (decP). The latter remains unaffected by EVT invasion. By defining a specific gating strategy, we report the accumulation of macrophages in decB. We describe a decidua basalis-associated macrophage (decBAM) population with a differential transcriptome and secretome compared with decidua parietalis-associated macrophages (decPAMs). decBAMs are CD11c and efficient inducers of Tregs, proliferate in situ, and secrete high levels of CXCL1, CXCL5, M-CSF, and IL-10. In contrast, decPAMs exert a dendritic cell-like, motile phenotype characterized by induced expression of HLA class II molecules, enhanced phagocytosis, and the ability to activate T cells. Strikingly, EVT-conditioned media convert decPAMs into a decBAM phenotype. These findings assign distinct macrophage phenotypes to decidual areas depending on placentation and further highlight a critical role for EVTs in the induction of decB-associated macrophage polarization.
Topics: Pregnancy; Female; Humans; Pregnancy Trimester, First; Decidua; Trophoblasts; Phenotype; Macrophages
PubMed: 36640334
DOI: 10.1016/j.celrep.2022.111977 -
Nature Jul 2023Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large,...
Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodelling (SAR). However, it remains a matter of debate regarding which immune and stromal cells participate in these interactions and how this evolves with respect to gestational age. Here we used a multiomics approach, combining the strengths of spatial proteomics and transcriptomics, to construct a spatiotemporal atlas of the human maternal-fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time-of-flight and a 37-plex antibody panel to analyse around 500,000 cells and 588 arteries within intact decidua from 66 individuals between 6 and 20 weeks of gestation, integrating this dataset with co-registered transcriptomics profiles. Gestational age substantially influenced the frequency of maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, galectin-9 and IDO-1 becoming increasingly enriched and colocalized at later time points. By contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting distinct monotonic and biphasic trends. Last, we developed an integrated model of SAR whereby invasion is accompanied by the upregulation of pro-angiogenic, immunoregulatory EVT programmes that promote interactions with the vascular endothelium while avoiding the activation of maternal immune cells.
Topics: Female; Humans; Pregnancy; Arteries; Decidua; Pregnancy Trimester, First; Trophoblasts; Uterus; Maternal-Fetal Exchange; Time Factors; Proteomics; Gene Expression Profiling; Datasets as Topic; Gestational Age
PubMed: 37468587
DOI: 10.1038/s41586-023-06298-9 -
Frontiers in Immunology 2022Patients with recurrent pregnancy loss (RPL) account for approximately 1%-5% of women aiming to achieve childbirth. Although studies have shown that RPL is associated... (Review)
Review
Patients with recurrent pregnancy loss (RPL) account for approximately 1%-5% of women aiming to achieve childbirth. Although studies have shown that RPL is associated with failure of endometrial decidualization, placental dysfunction, and immune microenvironment disorder at the maternal-fetal interface, the exact pathogenesis remains unknown. With the development of high-throughput technology, more studies have focused on the genomics, transcriptomics, proteomics and metabolomics of RPL, and new gene mutations and new biomarkers of RPL have been discovered, providing an opportunity to explore the pathogenesis of RPL from different biological processes. Bioinformatics analyses of these differentially expressed genes, proteins and metabolites also reflect the biological pathways involved in RPL, laying a foundation for further research. In this review, we summarize the findings of omics studies investigating decidual tissue, villous tissue and blood from patients with RPL and identify some possible limitations of current studies.
Topics: Abortion, Habitual; Decidua; Endometrium; Female; Humans; Placenta; Pregnancy; Proteomics
PubMed: 35572542
DOI: 10.3389/fimmu.2022.826198 -
International Journal of Molecular... Jun 2020Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the... (Review)
Review
Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the establishment of the pregnancy at the time of endometrial decidualization. Humans are one of only a few mammalian viviparous species in which decidualization begins during the latter half of each menstrual cycle and is therefore independent of the conceptus. Failure to adequately prepare (decidualize) the endometrium hormonally, biochemically, and immunologically in anticipation of the approaching blastocyst-including the downregulation of genes involved in the pro- inflammatory response and resisting tissue invasion along with the increased expression of genes that promote angiogenesis, foster immune tolerance, and facilitate tissue invasion-leads to abnormal implantation/placentation and ultimately to adverse pregnancy outcome. We hypothesize, therefore, that the primary driver of pregnancy health is the quality of the soil, not the seed.
Topics: Animals; Autocrine Communication; Biomarkers; Decidua; Embryo Implantation; Endometrium; Female; Gene Expression Regulation; Humans; Paracrine Communication; Placentation; Pregnancy; Pregnancy Complications; Pregnancy Outcome
PubMed: 32521725
DOI: 10.3390/ijms21114092