Morey Robert, Bui Tony, Cheung Virginia Chu, Dong Chen, Zemke Joseph E, Requena Daniela, Arora Harneet, Jackson Madeline G, Pizzo Donald, Theunissen Thorold W, Horii Mariko
Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA.
Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92093, USA.
iScience. 2024 Mar 25;27(4):109569. doi: 10.1016/j.isci.2024.109569. eCollection 2024 Apr 19.
Preeclampsia (PE) is a hypertensive pregnancy disorder with increased risk of maternal and fetal morbidity and mortality. Abnormal extravillous trophoblast (EVT) development and function is considered to be the underlying cause of PE, but has not been previously modeled . We previously derived induced pluripotent stem cells (iPSCs) from placentas of PE patients and characterized abnormalities in formation of syncytiotrophoblast and responses to changes in oxygen tension. In this study, we converted these primed iPSC to naïve iPSC, and then derived trophoblast stem cells (TSCs) and EVT to evaluate molecular mechanisms underlying PE. We found that primed (but not naïve) iPSC-derived PE-EVT have reduced surface HLA-G, blunted invasive capacity, and altered EVT-specific gene expression. These abnormalities correlated with promoter hypermethylation of genes associated with the epithelial-mesenchymal transition pathway, specifically in primed-iPSC derived PE-EVT. Our findings indicate that abnormal epigenetic regulation might play a role in PE pathogenesis.
子痫前期（PE）是一种妊娠期高血压疾病，会增加母婴发病和死亡风险。绒毛外滋养层细胞（EVT）发育和功能异常被认为是PE的根本原因，但此前尚未建立相关模型。我们之前从PE患者的胎盘衍生出诱导多能干细胞（iPSC），并对合体滋养层形成异常以及对氧张力变化的反应进行了表征。在本研究中，我们将这些已分化的iPSC转化为原始态iPSC，然后衍生出滋养层干细胞（TSC）和EVT，以评估PE潜在的分子机制。我们发现，已分化（而非原始态）的iPSC衍生的PE-EVT表面HLA-G减少、侵袭能力减弱且EVT特异性基因表达改变。这些异常与上皮-间质转化途径相关基因的启动子高甲基化有关，特别是在已分化iPSC衍生的PE-EVT中。我们的研究结果表明，异常的表观遗传调控可能在PE发病机制中起作用。
