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.
Sci Rep. 2021 Mar 15;11(1):5877. doi: 10.1038/s41598-021-85230-5.
Preeclampsia (PE) is a pregnancy-specific hypertensive disorder, affecting up to 10% of pregnancies worldwide. The primary etiology is considered to be abnormal development and function of placental cells called trophoblasts. We previously developed a two-step protocol for differentiation of human pluripotent stem cells, first into cytotrophoblast (CTB) progenitor-like cells, and then into both syncytiotrophoblast (STB)- and extravillous trophoblast (EVT)-like cells, and showed that it can model both normal and abnormal trophoblast differentiation. We have now applied this protocol to induced pluripotent stem cells (iPSC) derived from placentas of pregnancies with or without PE. While there were no differences in CTB induction or EVT formation, PE-iPSC-derived trophoblast showed a defect in syncytialization, as well as a blunted response to hypoxia. RNAseq analysis showed defects in STB formation and response to hypoxia; however, DNA methylation changes were minimal, corresponding only to changes in response to hypoxia. Overall, PE-iPSC recapitulated multiple defects associated with placental dysfunction, including a lack of response to decreased oxygen tension. This emphasizes the importance of the maternal microenvironment in normal placentation, and highlights potential pathways that can be targeted for diagnosis or therapy, while absence of marked DNA methylation changes suggests that other regulatory mechanisms mediate these alterations.
子痫前期 (PE) 是一种妊娠特有的高血压疾病，影响全球多达 10%的妊娠。其主要病因被认为是胎盘细胞（称为滋养细胞）的异常发育和功能。我们之前开发了一种两步法方案，用于将人类多能干细胞分化为滋养细胞前体细胞样细胞，然后分化为合体滋养层 (STB) 和细胞滋养层外胚层样细胞 (EVT)，并表明它可以模拟正常和异常的滋养细胞分化。我们现在已经将该方案应用于来自子痫前期或无子痫前期妊娠胎盘的诱导多能干细胞 (iPSC)。虽然 CTB 诱导或 EVT 形成没有差异，但 PE-iPSC 衍生的滋养细胞在合胞体化方面存在缺陷，并且对缺氧的反应迟钝。RNAseq 分析显示 STB 形成和对缺氧的反应缺陷；然而，DNA 甲基化变化很小，仅对应于对缺氧的反应变化。总体而言，PE-iPSC 重现了与胎盘功能障碍相关的多种缺陷，包括对低氧张力缺乏反应。这强调了母体微环境在正常胎盘形成中的重要性，并突出了可能成为诊断或治疗靶点的潜在途径，而 DNA 甲基化变化不明显表明其他调节机制介导了这些改变。
