He Jie, Yang Huan, Liu Zheng, Chen Miaomiao, Ye Ying, Tao Yuelan, Li Shuhong, Fang Jie, Xu Jiacheng, Wu Xiafei, Qi Hongbo
Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.
Front Mol Biosci. 2023 Sep 25;10:1248771. doi: 10.3389/fmolb.2023.1248771. eCollection 2023.
Preeclampsia (PE), a notable pregnancy-related disorder, leads to 40,000+ maternal deaths yearly. Recent research shows PE divides into early-onset (EOPE) and late-onset (LOPE) subtypes, each with distinct clinical features and outcomes. However, the molecular characteristics of various subtypes are currently subject to debate and are not consistent. We integrated transcriptomic expression data from a total of 372 placental samples across 8 publicly available databases via combat algorithm. Then, a variety of strategies including Random Forest Recursive Feature Elimination (RF-RFE), differential analysis, oposSOM, and Weighted Correlation Network Analysis were employed to identify the characteristic genes of the EOPE and LOPE subtypes. Finally, we conducted in vitro experiments on the key gene HK2 in HTR8/SVneo cells to explore its function. Our results revealed a complex classification of PE placental samples, wherein EOPE manifests as a highly homogeneous sample group characterized by hypoxia and HIF1A activation. Among the core features is the upregulation of glycolysis-related genes, particularly HK2, in the placenta-an observation corroborated by independent validation data and single-cell data. Building on the pronounced correlation between HK2 and EOPE, we conducted in vitro experiments to assess the potential functional impact of HK2 on trophoblast cells. Additionally, the LOPE samples exhibit strong heterogeneity and lack distinct features, suggesting a complex molecular makeup for this subtype. Unsupervised clustering analysis indicates that LOPE likely comprises at least two distinct subtypes, linked to cell-environment interaction and cytokine and protein modification functionalities. In summary, these findings elucidate potential mechanistic differences between the two PE subtypes, lend support to the hypothesis of classifying PE based on gestational weeks, and emphasize the potential significant role of glycolysis-related genes, especially HK2 in EOPE.
子痫前期（PE）是一种显著的妊娠相关疾病，每年导致4万多例孕产妇死亡。最近的研究表明，PE分为早发型（EOPE）和晚发型（LOPE）亚型，每种亚型都有独特的临床特征和结局。然而，目前各种亚型的分子特征存在争议且不一致。我们通过ComBat算法整合了来自8个公开可用数据库的总共372个胎盘样本的转录组表达数据。然后，采用了包括随机森林递归特征消除（RF-RFE）、差异分析、oposSOM和加权相关网络分析等多种策略来识别EOPE和LOPE亚型的特征基因。最后，我们在HTR8/SVneo细胞中对关键基因HK2进行了体外实验，以探索其功能。我们的结果揭示了PE胎盘样本的复杂分类，其中EOPE表现为一个高度同质的样本组，其特征是缺氧和HIF1A激活。核心特征之一是胎盘中糖酵解相关基因的上调，特别是HK⁃2，这一观察结果得到了独立验证数据和单细胞数据的证实。基于HK2与EOPE之间的显著相关性，我们进行了体外实验，以评估HK2对滋养层细胞的潜在功能影响。此外，LOPE样本表现出很强的异质性且缺乏明显特征，这表明该亚型的分子构成复杂。无监督聚类分析表明，LOPE可能至少包括两个不同的亚型，与细胞-环境相互作用以及细胞因子和蛋白质修饰功能有关。总之，这些发现阐明了两种PE亚型之间潜在的机制差异，支持了基于孕周对PE进行分类的假设，并强调了糖酵解相关基因，特别是HK2在EOPE中的潜在重要作用。
