Nonn Olivia, Debnath Olivia, Valdes Daniela S, Sallinger Katja, Secener Ali Kerim, Fischer Cornelius, Tiesmeyer Sebastian, Nimo Jose, Kuenzer Thomas, Ulrich Juliane, Maxian Theresa, Knöfler Martin, Karau Philipp, Bartolomaeus Hendrik, Kroneis Thomas, Frolova Alina, Neuper Lena, Haase Nadine, Malt Alexander, Müller-Bötticher Niklas, Kräker Kristin, Kedziora Sarah, Forstner Désirée, Eils Roland, Schmidt-Ullrich Ruth, Haider Sandra, Verlohren Stefan, Stern Christina, Sugulle Meryam, Jones Stuart, Thilaganathan Basky, Kaitu'u-Lino Tu'uhevaha J, Tong Stephen, Huppertz Berthold, El-Heliebi Amin, Staff Anne Cathrine, Coscia Fabian, Müller Dominik N, Dechend Ralf, Gauster Martin, Ishaque Naveed, Herse Florian
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., D.N.M., R.D., F.H.).
Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité - Universitätsmedizin Berlin, Germany (O.N., D.S.V., J.U., H.B., A.F., N.H., K.K., S.K., R.S.-U., D.N.M., R.D., F.H.).
Hypertension. 2025 May;82(5):787-799. doi: 10.1161/HYPERTENSIONAHA.124.23362. Epub 2024 Oct 23.
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.
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.
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 our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis.
This indicates that increased syncytiotrophoblast senescence appears weeks before clinical manifestation of early onset preeclampsia, suggesting that the dysregulated preeclamptic placenta starts with higher cell maturation resulting in premature and increased senescence-associated secretory phenotype release. These senescence-associated secretory phenotype markers may serve as an additional early diagnostic tool for this syndrome.
子痫前期是一种严重的妊娠期高血压疾病，可导致早产、母婴发病、死亡及终身后遗症。了解子痫前期的发病机制是保护母婴免受该综合征影响并降低其日后患心血管疾病风险的关键第一步。然而，针对子痫前期有效的早期预测检测方法和治疗手段却很匮乏。
为了识别早发型子痫前期的新型标志物和信号通路，我们采用单核RNA测序结合空间转录组学技术，对早发型子痫前期患者和健康对照的母胎界面单位（胎儿绒毛和母体蜕膜）进行了分析。胎盘合体滋养层直接与母体血液接触，形成胎儿与母体循环之间的屏障。
我们识别出内分泌合体滋养层细胞核的不同转录组状态，其失调模式与衰老相关分泌表型以及胎盘滋养层中衰老的空间失调有关。临床多中心队列的胎盘组织中验证了衰老标志物升高。重要的是，几种分泌型衰老相关分泌表型因子在孕早期母体血液中就已升高。我们验证了在单核RNA测序模型中识别出的分泌型衰老标志物纤溶酶原激活物抑制剂1（PAI-1）和激活素A，可作为临床子痫前期诊断前的预测标志物。
这表明合体滋养层衰老增加在早发型子痫前期临床表现出现数周前就已发生，提示子痫前期胎盘失调始于更高的细胞成熟度，导致过早且增加的衰老相关分泌表型释放。这些衰老相关分泌表型标志物可能成为该综合征的一种额外早期诊断工具。
