H3K27me3 调节的 Hofbauer 细胞 BMP2 信号增强可弥补子痫前期中浅绒毛膜侵袭。
H3K27me3-modulated Hofbauer cell BMP2 signalling enhancement compensates for shallow trophoblast invasion in preeclampsia.
机构信息
Center for Reproductive Medicine, Shandong University, Jinan, Shandong, 250012, China; Medical Integration and Practice Center, Shandong University, Jinan, Shandong, 250012, China.
Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China.
出版信息
EBioMedicine. 2023 Jul;93:104664. doi: 10.1016/j.ebiom.2023.104664. Epub 2023 Jun 16.
BACKGROUND
Preeclampsia (PE) is a common hypertensive pregnancy disorder associated with shallow trophoblast invasion. Although bone morphogenetic protein 2 (BMP2) has been shown to promote trophoblast invasion in vitro, its cellular origin and molecular regulation in placenta, as well as its potential role in PE, has yet to be established. Additionally, whether BMP2 and/or its downstream molecules could serve as potential diagnostic or therapeutic targets for PE has not been explored.
METHODS
Placentas and sera from PE and healthy pregnant women were subjected to multi-omics analyses, immunoblots, qPCR, and ELISA assays. Immortalized trophoblast cells, primary cultures of human trophoblasts, and first-trimester villous explants were used for in vitro experiments. Adenovirus expressing sFlt-1 (Ad Flt1)-induced PE rat model was used for in vivo studies.
FINDINGS
We find globally decreased H3K27me3 modifications and increased BMP2 signalling in preeclamptic placentas, which is negatively correlated with clinical manifestations. BMP2 is derived from Hofbauer cells and epigenetically regulated by H3K27me3 modification. BMP2 promotes trophoblast invasion and vascular mimicry by upregulating BMP6 via BMPR1A-SMAD2/3-SMAD4 signalling. BMP2 supplementation alleviates high blood pressure and fetal growth restriction phenotypes in Ad Flt1-induced rat PE model.
INTERPRETATION
Our findings demonstrate that epigenetically regulated Hofbauer cell-derived BMP2 signalling enhancement in late gestation could serve as a compensatory response for shallow trophoblast invasion in PE, suggesting opportunities for diagnostic marker and therapeutic target applications in PE clinical management.
FUNDING
National Key Research and Development Program of China (2022YFC2702400), National Natural Science Foundation of China (82101784, 82171648, 31988101), and Natural Science Foundation of Shandong Province (ZR2020QH051, ZR2020MH039).
背景
子痫前期（PE）是一种常见的妊娠高血压疾病，与浅着床的滋养细胞侵袭有关。虽然骨形态发生蛋白 2（BMP2）已被证明能促进滋养细胞在体外侵袭，但它在胎盘中的细胞起源和分子调控，以及其在 PE 中的潜在作用，尚未确定。此外，BMP2 及其下游分子是否可作为 PE 的潜在诊断或治疗靶点，尚未得到探索。
方法
PE 和健康孕妇的胎盘和血清进行了多组学分析、免疫印迹、qPCR 和 ELISA 检测。永生滋养细胞、人滋养细胞原代培养物和第一 trimester 绒毛外植体用于体外实验。腺病毒表达可溶性 Flt-1（Ad Flt1）诱导的 PE 大鼠模型用于体内研究。
发现
我们发现，PE 胎盘存在广泛的 H3K27me3 修饰减少和 BMP2 信号增加，与临床表现呈负相关。BMP2 来源于 Hofbauer 细胞，受 H3K27me3 修饰的表观遗传调控。BMP2 通过 BMPR1A-SMAD2/3-SMAD4 信号上调 BMP6，促进滋养细胞侵袭和血管模拟。BMP2 补充可减轻 Ad Flt1 诱导的 PE 大鼠模型中的高血压和胎儿生长受限表型。
结论
我们的研究结果表明，妊娠晚期受表观遗传调控的 Hofbauer 细胞衍生的 BMP2 信号增强可能是 PE 中浅滋养细胞侵袭的代偿反应，提示在 PE 临床管理中，BMP2 作为诊断标志物和治疗靶点的应用前景。
资助
国家重点研发计划（2022YFC2702400）、国家自然科学基金（82101784、82171648、31988101）和山东省自然科学基金（ZR2020QH051、ZR2020MH039）。
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