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

作者：Olivia Nonn, Olivia Debnath, Daniela S. Valdes, Katja Sallinger, Kerim Secener, Sandra Haider, Cornelius Fischer, Sebastian Tiesmeyer, Jose Nimo, Thomas Kuenzer, Theresa Maxian, Martin Knöfler, Philipp Karau, Hendrik Bartolomaeus, Thomas Kroneis, Alina Frolova, Lena Neuper, Nadine Haase, Kristin Kräker, Sarah Kedziora, Désirée Forstner, Stefan Verlohren, Christina Stern, Fabian Coscia, Meryam Sugulle, Stuart A. Jones, Basky Tilaganathan, Roland Eils, Berthold Huppertz, Amin El‐Heliebi, Anne Cathrine Staff, Dominik N. Müller, Ralf Dechend, Martin Gauster, Naveed Ishaque, Florian Herse · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2022 · DOI：10.1101/2022.10.10.511539 · 被引用次数：6 · 研究领域：Pregnancy and preeclampsia studies、Birth, Development, and Health、Reproductive System and Pregnancy

Summary 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 1 . We currently lack efficient screening tools 2, 3 and early therapies 4, 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 d...