Single Cell Analysis of the Human Placenta
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ABSTRACT: Over 135 million births occur each year; yet, the molecular underpinnings of human parturition in gestational tissues, and in particular the placenta, are still poorly understood. The placenta is a complex heterogeneous organ including cells of both maternal and fetal origin, and insults that disrupt the maternal-fetal dialogue could result in adverse pregnancy outcomes such as preterm birth. There is limited knowledge of the cell type composition and transcriptional activity of the placenta and its compartments during physiologic and pathologic parturition. To fill this knowledge gap, we used scRNA-seq to profile the placental villous tree, basal plate, and chorioamniotic membranes of women with or without labor at term and those with preterm labor.
REPOSITORIES: dbGaP
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Project description:Preeclampsia (PE), which affects 4-8% of human pregnancies, causes significant maternal and neonatal morbidity and mortality. Within the basal plate, placental cytotrophoblasts (CTBs) of fetal origin invade the uterus and extensively remodel the maternal vasculature. In PE, CTB invasion is often shallow, and vascular remodeling is rudimentary. To better understand possible causes, we conducted a global analysis of gene expression at the maternal-fetal interface in placental samples from women with PE (n = 12; 24-36 wk) vs. samples from women who delivered due to preterm labor with no evidence of infection (n = 11; 24-36 wk), a condition that our previous work showed is associated with normal CTB invasion. Using the HG-U133A&B Affymetrix GeneChip platform, and statistical significance set at log odds-ratio of B >0, 55 genes were differentially expressed in PE. They encoded proteins previously associated with PE [e.g. Flt-1 (vascular endothelial growth factor receptor-1), leptin, CRH, and inhibin] and novel molecules [e.g. sialic acid binding Ig-like lectin 6 (Siglec-6), a potential leptin receptor, and pappalysin-2 (PAPP-A2), a protease that cleaves IGF-binding proteins]. We used quantitative PCR to validate the expression patterns of a subset of the genes. At the protein level, we confirmed PE-related changes in the expression of Siglec-6 and PAPP-A2, which localized to invasive CTBs and syncytiotrophoblasts. Notably, Siglec-6 placental expression is uniquely human, as is spontaneous PE. The functional significance of these novel observations may provide new insights into the pathogenesis of PE, and assaying the circulating levels of these proteins could have clinical utility for predicting and/or diagnosing PE. Keywords: disease state analysis Basal plate biopsies of preterm labor (24-36 weeks; n=11) and preterm severe preeclampsia (24-36 weeeks; n=12) were isolated and the global gene expression profiles determined using Affymetrix Human GeneChips. Comparisons between the preeclampsia samples and the preterm labor controls revealed genes differentially expressed in preeclampsia.
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Project description:Preterm birth is a leading cause of neonatal morbidity and mortality. Microbial infection and inflammation of the amniotic cavity are associated with the majority of early preterm births and thought to arise from ascension of bacteria from the lower genital tract. Group B Streptococci (GBS) are beta-hemolytic, gram-positive bacteria, which commonly colonize the vagina and have been recovered from the amniotic fluid in cases of preterm birth. Host immune defenses that are critical for prevention of microbial invasion of the amniotic cavity (MIAC) and preterm labor are not completely understood. We recently showed that increased expression of the hemolytic pigment promotes GBS penetration of human placenta ex vivo and hyperhemolytic/hyperpigmented GBS strains with mutations in the hemolysin repressor (CovR/CovS) can be isolated from women in preterm labor. To understand placental/ choriodecidual immune responses that are necessary to prevent MIAC and preterm labor, we utilized a unique chronically catheterized nonhuman primate model that closely emulates human pregnancy. We observed that preterm labor, MIAC, and fetal injury occurred significantly more frequently in pregnant nonhuman primates infected with hyperpigmented GBS (ΔcovR) despite the strong induction of proinflammatory responses in the chorioamnion. Placental histopathology revealed a systematic progression in development of chorioamnionitis in GBSΔcovR animals beginning with chorionic vasculitis and subsequently progressing to neutrophilic infiltration in the chorioamnion.
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Project description:Maternal obesity in mice negatively affects placental functionand maternal and fetal liver function. We performed a global proteomic analysis using a liquid-chromatography/mass-spectrometry system to investigate total and phosphorylated proteins in the placenta and fetal liver in a mouse model that combines maternal obesity with maternal androgen excess to identify changes in molecular pathways that might promote diseases in adulthood.
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Project description:Myostatin (gene symbol: <i>Mstn</i>) is an autocrine and paracrine inhibitor of muscle growth. Pregnant mice with genetically reduced levels of myostatin give birth to offspring with greater adult muscle mass and bone biomechanical strength. However, maternal myostatin is not detectable in fetal circulations. Fetal growth is dependent on the maternal environment, and the provisioning of nutrients and growth factors by the placenta. Thus, this study examined the effect of reduced maternal myostatin on maternal and fetal serum metabolomes, as well as the placental metabolome. Fetal and maternal serum metabolomes were highly distinct, which is consistent with the role of the placenta in creating a specific fetal nutrient environment. There was no effect from myostatin on maternal glucose tolerance or fasting insulin. In comparisons between pregnant control and <i>Mstn</i><sup>+/-</sup> mice, there were more significantly different metabolite concentrations in fetal serum, at 50, than in the mother's serum at 33, confirming the effect of maternal myostatin reduction on the fetal metabolic milieu. Polyamines, lysophospholipids, fatty acid oxidation, and vitamin C, in fetal serum, were all affected by maternal myostatin reduction.
2023-06-08 | MTBLS3345 | MetaboLights
Project description:Preterm birth is a main determinant of neonatal mortality and morbidity and a major contributor to the overall mortality and burden of disease. However, precise phenotyping of the preterm birth is hampered by the imprecise definition of the clinical phenotype and complexity of the molecular phenotype due to multiple pregnancy tissue types and molecular processes that may contribute to the preterm birth. The studyâ??s aim was to comprehensively evaluate the mRNA transcriptome that characterizes preterm and term labor using precisely phenotyped samples. Expression profiles of 73 genes and non-coding RNA sequences uniquely identified the four groups of patients: delivering preterm with (PL) and without labor (PNL), term with (TL) and without labor (TNL). The largest differences in gene expression among the four groups occurred in decidua, chorion and amnion. The gene expression profiles showed suppression of chemokines expression in TNL, withdrawal of this suppression in TL, activation of multiple pathways of inflammation in PL, and an immune rejection profile in PNL. The genes constituting expression signatures showed over-representation of three putative regulatory elements in their 5â?? and 3â??UTR regions. The results suggest that pregnancy is maintained by downregulation of chemokines at the maternal-fetal interface. Withdrawal of this downregulation results in the term birth and its overriding by the activation of multiple pathways of the immune system in the preterm birth. Complications of the pregnancy associated with impairment of placental function, which necessitated premature delivery of the fetus in the absence of labor, show gene expression patterns associated with immune rejection. 183 total RNA samples from 8 tissue types collected from 35 women grouped into six categories of pregnancy outcome. One microarray replicate per sample. Other Contributors: Radek Bukowski, Sam Parry and the NICHD Genomic and Proteomic Network for Preterm Birth Research
2016-06-30 | E-GEOD-73685 | biostudies-arrayexpress
Project description:The placenta regulates maternal-fetal communication, and its defect leads to significant pregnancy complications. The maternal and embryonic circulations are primitively connected in early placentation, but the function of the placenta during this developmentally essential period is relatively unknown. We thus performed a comparative proteomic analysis of the placenta before and after primary placentation and found that the metabolism and transport of lipids were characteristically activated in this period. The placental fatty acid (FA) carriers in specific placental compartments were upregulated according to gestational age, and metabolomic analysis also showed that the placental transport of FAs increased in a time-dependent manner. Further analysis of two mutant mice models with embryonic lethality revealed that lipid-related signatures could reflect the functional state of the placenta. Our findings highlight the importance of the nutrient transport function of the primary placenta in the early gestational period and the role of lipids in embryonic development.
2023-09-06 | PXD026858 | Pride
Project description:The goal of this study was to transcriptionally profile the three layers of the human placenta (decidua, fetal membrane and placental villi) from preterm and term human placentas
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Project description:Background: Maternal iron deficiency (ID) is associated with poor pregnancy and fetal outcomes. The effect is thought to be mediated by the placenta but there is no comprehensive assessment of placental response to maternal ID. Additionally, whether the influence of maternal ID on the placenta differs by fetal sex is unknown. Objectives: Our primary aim was to identify gene and protein signatures of ID mouse placentas at mid-gestation. A secondary objective was to profile the expression of iron genes in mouse placentas across gestation. Methods: We used a real-time PCR based array to determine the mRNA expression of all known iron genes in mouse placentas at embryonic day (E) 12.5, E14.5, E16.5, and E19.5 (n=3 placentas/time point). To determine the effect of maternal ID, we performed RNA sequencing and proteomics in male and female placentas from ID and iron adequate mice at E12.5 (n=8 dams/diet). Results: In female placentas, six genes including transferrin receptor (Tfrc) and solute carrier family 11 member 2 were significantly changed by maternal ID. An additional 154 genes were altered in male ID placentas. Proteomic analysis quantified 7662 proteins in the placenta. Proteins translated from iron responsive element (IRE) containing mRNAs were altered in abundance; ferritin and ferroportin 1 decreased while TFRC increased in ID placenta. Less than 4% of the significantly altered genes in ID placentas occurred both at the transcriptional and translational levels. Conclusions: Our data demonstrate that the impact of maternal ID on placental gene expression in mice is limited in scope and magnitude at mid-gestation. We provide strong evidence for IRE-based transcriptional and translational coordination of iron gene expression in the mouse placenta. Finally, we discover sexually dimorphic effects of maternal ID on placental gene expression, with more genes and pathways altered in male compared with female mouse placentas.
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2021-02-25 | GSE167429 | GEO
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2021-02-25 | GSE167412 | GEO