Senescent Syncytiotrophoblast Secretion During Early Onset Preeclampsia

作者：Olivia Nonn, Olivia Debnath, Daniela S. Valdes, Katja Sallinger, Kerim Secener, Cornelius Fischer, Sebastian Tiesmeyer, Jose Nimo, Thomas Kuenzer, Juliane Ulrich, Theresa Maxian, Martin Knöfler, Philipp Karau, Hendrik Bartolomaeus, Thomas Kroneis, Alina Frolova, Lena Neuper, Nadine Haase, Alexander Malt, Niklas Müller‐Bötticher, Kristin Kräker, Sarah Kedziora, Désirée Forstner, Roland Eils, Ruth Schmidt‐Ullrich, Sandra Haider, Stefan Verlohren, Christina Stern, Meryam Sugulle, Stuart Jones, B. Thilaganathan, Tu’uhevaha J. Kaitu’u‐Lino, Stephen Tong, Berthold Huppertz, Amin El‐Heliebi, Anne Cathrine Staff, Fabian Coscia, Dominik N. Müller, Ralf Dechend, Martin Gauster, Naveed Ishaque, Florian Herse · 发表于：Hypertension · 年份：2024 · DOI：10.1161/hypertensionaha.124.23362 · 被引用次数：28 · 研究领域：Pregnancy and preeclampsia studies、Preterm Birth and Chorioamnionitis、Telomeres, Telomerase, and Senescence

BACKGROUND: Preeclampsia is a severe hypertensive disorder in pregnancy that causes preterm delivery, maternal and fetal morbidity, mortality, and life-long sequelae. Understanding the pathogenesis of preeclampsia is a critical first step toward protecting mother and child from this syndrome and increased risk of cardiovascular disease later in life. However, effective early predictive tests and therapies for preeclampsia are scarce. METHODS: To identify novel markers and signaling pathways for early onset preeclampsia, we profiled human maternal-fetal interface units (fetal villi and maternal decidua) from early onset preeclampsia and healthy controls using single-nucleus RNA sequencing combined with spatial transcriptomics. The placental syncytiotrophoblast is in direct contact with maternal blood and forms the barrier between fetal and maternal circulation. RESULTS: We identified different transcriptomic states of the endocrine syncytiotrophoblast nuclei with patterns of dysregulation associated with a senescence-associated secretory phenotype and a spatial dysregulation of senescence in the placental trophoblast layer. Elevated senescence markers were validated in placental tissues of clinical multicenter cohorts. Importantly, several secreted senescence-associated secretory phenotype factors were elevated in maternal blood already in the first trimester. We verified the secreted senescence markers, PAI-1 (plasminogen activator inhibitor 1) and activin A, as identified in...