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Disturbed trophoblast transition links early fetal to maternal syndrome progression in pre-eclampsia

ABSTRACT: Pre-eclampsia (PE) is a syndrome that affects multiple organ systems and is the most severe hypertensive disorder in pregnancy. It frequently leads to preterm delivery, maternal and fetal morbidity and mortality, and life-long complications. We currently lack efficient screening tools and early therapies to address PE. To study the initial stages of early onset PE and identify candidate markers and pathways, we performed spatio-temporal multi-omics profiling of human PE placentae and healthy controls and validated targets in early gestation in a longitudinal clinical cohort. We used a single nuclei RNA-seq approach combined with spatial proteo- and transcriptomics and mechanistic in vitro signaling analyses. We discovered a key disruption in trophoblast transition, which is driven by the increase of transcriptional coactivator p300 that ultimately ends with a senescence-associated secretory phenotype (SASP) of trophoblasts. We found a significant increase in the senescence marker Activin-A in preeclamptic maternal serum in early gestation, before the development of clinical symptoms, indicating a translation of the fetal syndrome to the maternal side. Our work identifies potential new biomarkers for the early diagnosis of the disease and possible targets for interventions, which would be crucial steps toward protecting the mother and child from gestational mortality and morbidity and an increased risk of cardiovascular disease later in life. This study includes early placentae samples from the fetal part (villi; n=10), maternal part (Decidua; n=3), late placentae samples from healthy pregnancies, villi (n=6), decidua (n=4), and late placentae samples from early onset preeclamptic pregnancies, villi (n=5) and decidua (n=5).

PROVIDER: EGAS00001005681 | EGA |

REPOSITORIES: EGA

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Project description:Purpose: Next generation bulk RNA sequencing of a large group (37 individuals) of matched tissues (fetal brain and fetal placenta) from human fetuses collected via elective termination at 72-82 days post conception (d.p.c.), a timeframe that closely matches the embryonic developmental window used in our mouse studies (14.5-16.5) Methods: Human placenta (maternal decidua separated from fetal placenta) and fetal brain tissues were obtained from the NIH-supported Laboratory of Developmental Biology at the University of Washington between the years 1999 and 2010 and used under a protocol approved by the Duke University Institutional Review Board (Pro00014066). Tissue specimens were stored at -80°C until required for RNA or protein extraction. Prior to collection, informed consent was obtained from all individuals undergoing the elective termination. RNA from human tissue was prepared for sequencing using an Illumina TrueSeq RNA Exome kit and sequenced on an Illumina NovaSeq 6000 configured for a S2 flow cell at 50bp PE. Results: PCR for the Y chromosome (SRY) identified 17 male and 20 female fetal tissue sets, with the average age of 78.2 d.p.c. for both sexes. No maternal data were available, so we assessed decidual triglyceride accumulation to use as a proxy for maternal weight, given that women with overweight/obesity exhibit triglyceride accumulation in the placenta. Triglyceride levels trended higher in pregnancies with female fetuses, but there was no significant difference between triglyceride accumulation in decidua associated with male or female pregnancies. Pearson's Correlation of gene expression with maternal triglyceride accumulation from bulk RNA-seq from 16 matched male and 19 matched female brain and placenta samples revealed a strong dimorphic trend in gene expression. In male pregnancies, differentially correlated genes were predominantly over-expressed with increasing maternal weight (i.e. gene expression increased as maternal triglycerides increased); the opposite effect was seen in female pregnancies. In the male brain, only 45 genes significantly correlated with maternal triglyceride accumulation (either positive or negative), whereas 781 genes were significantly correlated in females.

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Disturbed trophoblast transition links early fetal to maternal syndrome progression in pre-eclampsia

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