Project description:Data on the temporal dynamics of human placental gene expression is scarce. We have completed the first whole-genome profiling of human placental gene expression dynamics (GeneChips, Affymetrix®) from early to mid- gestation (10 samples; gestational weeks 5 to 18) and report 154 genes with considerable change in transcript levels (FDR P<0.1). Functional enrichment analysis revealed >200 GO categories that are statistically over-represented among 105 genes with dynamically increasing transcript levels. Analysis in an extended sample (n=43; gestational weeks 5 to 41) conformed a highly significant (FDR P<0.05) expressional peak in mid-gestation placenta for ten genes: BMP5, CCNG2, CDH11, FST, GATM, GPR183, ITGBL1, PLAGL1, SLC16A10, STC1. A central hypothesis of our study states that the aberrant expression of genes characteristic to mid-gestation placenta may contribute to affected fetal growth, maternal preeclampsia (PE) or gestational diabetes (GD). The gene STC1 coding for Stanniocalcin 1 (STC1) was identified with a sharp placental expressional peak in mid-gestation, increased mRNA levels at term and significantly elevated STC1 protein levels in post-partum maternal plasma in all pregnancy complications. The highest STC1 levels were identified in women, who developed simultaneously PE and delivered an SGA baby (median 731 vs 418 pg/ml in controls; P=0.001). CCNG2 and LYPD6 exhibited significantly increased placental mRNA expression and enhanced intensity of immunohistochemistry staining in placental sections all studied in GD and PE cases. Aberrant expression of mid-gestation specific genes in pregnancy complications at term indicates the importance of the fine-scale tuning of the temporal dynamics of transcription regulation in placenta. Observed significantly elevated plasma STC1 in complicated pregnancies warrants further investigations of its potential as a biomarker. Interestingly, a majority of genes with high expression in mid-gestation placenta have also been implicated in adult complex disease. This observation promotes a recently opened discussion on the role of placenta in developmental programming. 4 samples; this submission is extension of our earlier study (accession GSE22490).

Project description:Data on the temporal dynamics of human placental gene expression is scarce. We have completed the first whole-genome profiling of human placental gene expression dynamics (GeneChips, Affymetrix®) from early to mid- gestation (10 samples; gestational weeks 5 to 18) and report 154 genes with considerable change in transcript levels (FDR P<0.1). Functional enrichment analysis revealed >200 GO categories that are statistically over-represented among 105 genes with dynamically increasing transcript levels. Analysis in an extended sample (n=43; gestational weeks 5 to 41) conformed a highly significant (FDR P<0.05) expressional peak in mid-gestation placenta for ten genes: BMP5, CCNG2, CDH11, FST, GATM, GPR183, ITGBL1, PLAGL1, SLC16A10, STC1. A central hypothesis of our study states that the aberrant expression of genes characteristic to mid-gestation placenta may contribute to affected fetal growth, maternal preeclampsia (PE) or gestational diabetes (GD). The gene STC1 coding for Stanniocalcin 1 (STC1) was identified with a sharp placental expressional peak in mid-gestation, increased mRNA levels at term and significantly elevated STC1 protein levels in post-partum maternal plasma in all pregnancy complications. The highest STC1 levels were identified in women, who developed simultaneously PE and delivered an SGA baby (median 731 vs 418 pg/ml in controls; P=0.001). CCNG2 and LYPD6 exhibited significantly increased placental mRNA expression and enhanced intensity of immunohistochemistry staining in placental sections all studied in GD and PE cases. Aberrant expression of mid-gestation specific genes in pregnancy complications at term indicates the importance of the fine-scale tuning of the temporal dynamics of transcription regulation in placenta. Observed significantly elevated plasma STC1 in complicated pregnancies warrants further investigations of its potential as a biomarker. Interestingly, a majority of genes with high expression in mid-gestation placenta have also been implicated in adult complex disease. This observation promotes a recently opened discussion on the role of placenta in developmental programming.

Project description:Cell-to-cell communication is essential for the spiral artery (SpA) remodeling and required for maternal transfer of nutrient and oxygen to the fetus. Extravillous trophoblast invade the uterine arteries to remodel the SpA during the first 20 weeks of gestation. Interestingly, oxygen tenstion in the uterine environment changes with the progression of pregnancies and damage in the SpA remodelling can lead to preeclampsia and pther pregnancy complications. Recently, our understanding of how cells communicate has undergone a paradigm shift since the recognition of the role of exosomes on intercellular signaling. Here, we investigated whether oxygen tension alters the exosome release and miRNA profile from extravillous trophoblast (EVT), modifying their bioactivity on endothelial cells. Furthermore, we have established the exosomal miRNA profile at early gestation in women who develop pre-eclampsia (PE) and spontaneous preterm birth (SPTB). The effect of oxygen tension (i.e. 8% and 1% oxygen) on exosome release was quantified using nanocrystals (Qdot®) coupled to CD63 by fluorescence NTA. A real-time, live-cell imaging system (Incucyte™) was used to establish the effect of exosomes on endothelial cells. Plasma samples were obtained at early gestation (<18 weeks) and classified according to pregnancy outcomes. An Illumina TrueSeq Small RNA kit was used to construct a small RNA library from exosomal RNA obtained from EVT and plasma samples. The number of exosomes was significantly hifger in EVT culturedunder 1% compared to 8% oxygen. In total, 741 miRNA were identified in exosomes from EVT. Bioinformatic analysis revealed that these miRNA were associated with cell migration and cytokine production. Interestingly, exosomes isolated from EVT cultured at 8% oxygen increased EC migration, while exosomes from 1% oxygen decrease EC migration. These changes were inversely proportional to TNF-α released from EC. Finally, we have identified a set of uniques miRNA in exosomes from EVT cultured at 1% oxygen and exosomes isolated from maternal at early gestation, who developed PE and SPTB later in pregnancy. We suggest that aberrant exosomal signalling by placental cells is a common aetiological factor in pregnancy complications characterised by incomplete SpA remodeling and is therefore a clinically useful biomarker of pregnancy complications.

Project description:Background: Platelets may be pivotal mediators of the thrombo-haemorrhagic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. While gestational hypertension (GH) falls within the spectrum of hypertensive complications of pregnancy and is a risk factor for preeclampsia, it is unclear what biomarkers distinguish PE from GH. Aim: To identify specific plasma and platelet thrombo-inflammatory biomarkers indicative of preeclampsia and distinguish PE from GH. Methods: We performed multiplex immunoassays, assessed platelet and plasma proteomics and metabolomics data of PE patients, and compared with non-pregnant (NP), healthy pregnant (PC) and GH participants. Results: We report plasma proteins upregulated, enriched plasma metabolites and proteins distinctly overexpressed in platelets of PE and GH compared to NP and PC. Whilst procoagulation in PC may be fibrinogen driven, Inter-Alpha-Trypsin Inhibitors ITIH2 and ITIH3 were enriched in hypertensive complications of pregnancy (PE and GH), and fibronectin and S100A8/9 may be major procoagulant agonists in PE but not GH. In addition, platelet leucine-rich repeat-containing protein 27 and 42 (LRRC27/42) subunits of volume-regulated VRAC anion channels were markedly overexpressed in preeclampsia and may contribute to the heightened glucose sensitivity and the pro-thrombotic tendency of this disorder. Additionally, our multiplex immunoassays confirmed previous reports of increases in preeclampsia plasma cytokines, including SDF-1α, which can directly activate platelets; but also, i-309 and CTACK cytokines, whose effects on platelets we explored using STRING analysis. Conclusion: We identified biomarkers that may be monitored for preeclampsia onset and progression, and distinguish PE from GH. Also, through protein-protein interactions analysis, we generated a new hypothesis for platelets’ contribution to the thrombo-inflammatory states of preeclampsia.

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Characterization of human plasma pregnancy-associated miRNAs at first trimester and their association with pregnancy complications [cohort 2]

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