Modelling preeclampsia: a comparative analysis of the common human trophoblast cell lines.
Modelling preeclampsia: a comparative analysis of the common human trophoblast cell lines.
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DOI：
10.1096/fba.2020-00057
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发表时间：
2021-01
影响因子：
2.7
通讯作者：
Yu JY
中科院分区：
文献类型：
--
作者：
Zhao J;Chow RP;McLeese RH;Hookham MB;Lyons TJ;Yu JY
先兆子痫仍然是一个挑战，没有有效的治疗。证据支持可溶性fms样酪氨酸激酶-1（sFlt-1）和可溶性内皮糖蛋白（sEng）的靶向性，它们在缺血和缺氧应激下从胎盘过度释放。我们比较了四种滋养层细胞系BeWo，Jar，Jeg-3和HTR-8/SVneo，以确定用于药物筛选的合适模型。将培养的滋养层细胞暴露于1%氧气与常氧环境中24 - 48小时;包括人脐静脉和主动脉内皮细胞进行比较。通过ELISA测量上清液sFlt-1和sEng浓度，并通过RT-PCR测定sFlt-1 mRNA表达。探索了对实验治疗的细胞反应。所有四个滋养层细胞系分泌的sEng，这并没有增加缺氧。BeWo、Jar和Jeg-3在缺氧时表现出显著增强的sFlt-1 i13和e15 a mRNA表达;然而，只有BeWo释放了可检测水平的sFlt-1蛋白，其在缺氧时加倍。与此相反，缺氧降低HTR-8/SVneo中sFlt-1 mRNA表达和蛋白释放，与内皮细胞相似。其细胞机制与HIFα有关。BeWo对代表性药物的反应与文献中的人原代胎盘组织相似。这些数据支持BeWo‐缺氧模型模拟了先兆子痫的关键致病机制，并具有潜在的转化药物发现价值。
Preeclampsia remains a challenge without an effective therapy. Evidence supports targetability of soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and soluble endoglin (sEng), which are released excessively from the placenta under ischemic and hypoxic stresses. We compared four trophoblast cell lines, BeWo, Jar, Jeg‐3, and HTR‐8/SVneo, in order to identify a suitable model for drug screening. Cultured trophoblasts were exposed to 1% oxygen vs. normoxia for 24‐48 hr; human umbilical vein and aortic endothelial cells were included for comparison. Supernatant sFlt‐1 and sEng concentrations were measured by ELISA, and sFlt‐1 mRNA expression determined by RT‐PCR. Cellular responses to experimental therapeutics were explored. All four trophoblast lines secreted sEng, which did not increase by hypoxia. BeWo, Jar, and Jeg‐3 exhibited significantly enhanced expression of sFlt‐1 i13 and e15a mRNA in response to hypoxia; however, only BeWo released a detectable level of sFlt‐1 protein, which was doubled by hypoxia. In contrast, hypoxia decreased sFlt‐1 mRNA expression and protein release in HTR‐8/SVneo, similarly to endothelial cells. The cellular mechanism involved HIFα. BeWo responded to representative agents similarly to human primary placental tissues in the literature. These data support that the BeWo‐hypoxia model mimics a key pathogenic mechanism of preeclampsia and has potential value for translational drug discovery.