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 our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis. CONCLUSIONS 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.

中文翻译：

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早发性子痫前期的衰老合体滋养层分泌物。


背景 子痫前期是一种严重的妊娠期高血压疾病，可导致早产、母体和胎儿发病率、死亡率和终身后遗症。了解子痫前期的发病机制是保护母亲和孩子免受这种综合征和以后生活中心血管疾病风险增加的关键第一步。然而，针对子痫前期的有效早期预测测试和治疗很少。方法 为了确定早发性子痫前期的新标志物和信号通路，我们使用单核 RNA 测序结合空间转录组学分析了来自早发性子痫前期和健康对照的人母胎界面单位 （胎儿绒毛和母体蜕膜）。胎盘合体滋养层细胞与母体血液直接接触，并在胎儿和母体循环之间形成屏障。结果我们确定了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的分泌表型和胎盘滋养层衰老的空间失调相关。在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，在妊娠早期，母体血液中的几种分泌性衰老相关分泌表型因子已经升高。我们验证了在我们的单核 RNA 测序模型中确定的分泌的衰老标志物 PAI-1 （纤溶酶原激活物抑制剂 1） 和激活素 A，作为临床子痫前期诊断前的预测标志物。 结论 这表明合体滋养层衰老增加出现在早发性子痫前期临床表现前数周，表明失调的子痫前期胎盘从较高的细胞成熟开始，导致衰老相关分泌表型释放过早和增加。这些与衰老相关的分泌表型标志物可作为该综合征的额外早期诊断工具。