Huppertz, B. | Search bioRxiv

bioRxiv2025

Placental immune factors change during the first half of healthy pregnancy

During gestation, the human placenta develops as a fetal organ in direct contact with maternal cells and tissues. Most pregnancy complications, such as preeclampsia and fetal growth restriction, have their roots early in pregnancy, most probably in dysregulation of placental development and/or disturbances in the interaction with maternal (immune) cells. Here, we applied an integrative analysis of open-access gene expression data on the human placenta, comparing expression levels between the first and second trimesters of healthy pregnancy, with a focus on differentially expressed genes related to immune processes. The holistic approach of our study revealed differentially expressed genes involved in the recognition and elimination of potential PAMPs and DAMPs, transendothelial cell migration, cytokine production, transplacental IgG transport, and maintenance of immune tolerance during the transition from the first to the second trimester of placental development. Most DEGs show an increased expression. Only a few genes, DEFB1, SLPI, and LCN2, which encode antimicrobial proteins, homeostatic chemokines, and a pleiotropic PAEP that maintains tolerance, display maximal expression in the first trimester, followed by further down-regulation. The cell types deconvolutions revealed the typical representation of placental cells.

bioinformatics↗

bioRxiv2022

Disturbed trophoblast transition links preeclampsia progression from placenta to the maternal syndrome

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 complications1. We currently lack efficient screening tools2, 3 and early therapies4, 5 to address PE. To investigate the early 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 signalling analyses to bridge the gap from late pregnancy disease to early pregnancy pathomechanisms. We discovered a key disruption in villous trophoblast differentiation, 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 placental syndrome to the maternal side. Our work describes a new disease progression, starting with a disturbed transition in villous trophoblast differentiation. Our study identifies potential pathophysiology-relevant biomarkers for the early diagnosis of the disease as well as 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.

systems biology↗