Admati Inbal, Skarbianskis Niv, Hochgerner Hannah, Ophir Osnat, Weiner Zeev, Yagel Simcha, Solt Ido, Zeisel Amit
Faculty of Biotechnology and Food Engineering, Technion Israel Institute of Technology, Haifa, Israel.
Department of Obstetrics and Gynecology, Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
Med. 2023 Oct 13;4(10):687-709.e7. doi: 10.1016/j.medj.2023.07.005. Epub 2023 Aug 11.
Preeclampsia is a multisystemic, pregnancy-specific disorder united by new-onset hypertension but with considerable variation in clinical manifestation, onset, and severity. For symptoms to regress, delivery of the placenta is required. For symptoms to regress, delivery of the placenta is required, making the placenta central to preeclampsia pathophysiology. To dissect which placental functions were impacted in two forms of preeclampsia, we studied molecular changes across the cell types of the placenta.
We performed a transcriptomic survey of single-cells and single-nuclei on cases of early- and late-onset preeclampsia with gestation-matched controls.
Our data revealed massive dysregulation of gene expression in all cell classes that was almost exclusive to early preeclampsia. For example, an important known receptor/ligand imbalance hallmarking angiogenic disfunction, sFLT1/placental growth factor (PGF), was reflected in striking, cell-autonomous dysregulation of FLT1 and PGF transcription in the syncytium in early preeclampsia only. Stromal cells and vasculature echoed an inflamed, stressed, anti-angiogenic environment. Finally, the placental immune niche set the tone for inflammation in early but not late preeclampsia. Here, fetal-origin Hofbauer and maternal-origin TREM2 macrophages were revealed as surprising main actors, while local cells of the adaptive immune system were largely unaffected. Late preeclampsia showed minimal cellular impact on the placenta.
Our survey provides systematic molecular evidence for two distinct diseases. We resolved systematic molecular dysregulation to individual cell types with strong implications for definition, early detection, diagnosis, and treatment.
Funded by the Preeclampsia Foundation through the Peter Joseph Pappas Research Grant.
子痫前期是一种多系统的、妊娠特有的疾病，其共同特征是新发高血压，但临床表现、发病时间和严重程度存在很大差异。要使症状消退，需要娩出胎盘。胎盘娩出是症状消退的必要条件，这使得胎盘成为子痫前期病理生理学的核心。为了剖析两种子痫前期形式中哪些胎盘功能受到影响，我们研究了胎盘各细胞类型的分子变化。
我们对早发型和晚发型子痫前期病例以及妊娠匹配的对照进行了单细胞和单细胞核转录组学调查。
我们的数据显示，所有细胞类型中的基因表达均存在大量失调，这几乎是早发型子痫前期所特有的。例如，一种重要的、已知的受体/配体失衡标志着血管生成功能障碍，即可溶性血管内皮生长因子受体1（sFLT1）/胎盘生长因子（PGF），仅在早发型子痫前期的合体滋养层细胞中，FLT1和PGF转录出现显著的、细胞自主的失调中得到体现。基质细胞和脉管系统呈现出炎症、应激、抗血管生成的环境。最后，胎盘免疫微环境在早发型而非晚发型子痫前期中引发炎症。在这里，源自胎儿的霍夫鲍尔细胞和源自母体的触发受体表达2（TREM2）巨噬细胞被证明是令人惊讶的主要参与者，而适应性免疫系统的局部细胞基本未受影响。晚发型子痫前期对胎盘的细胞影响最小。
我们的调查为这两种不同的疾病提供了系统的分子证据。我们将系统的分子失调解析到个体细胞类型，这对定义、早期检测、诊断和治疗具有重要意义。
由子痫前期基金会通过彼得·约瑟夫·帕帕斯研究资助提供资金。
