iScience (Apr 2024)

iPSC-based modeling of preeclampsia identifies epigenetic defects in extravillous trophoblast differentiation

  • Robert Morey,
  • Tony Bui,
  • Virginia Chu Cheung,
  • Chen Dong,
  • Joseph E. Zemke,
  • Daniela Requena,
  • Harneet Arora,
  • Madeline G. Jackson,
  • Donald Pizzo,
  • Thorold W. Theunissen,
  • Mariko Horii

Journal volume & issue
Vol. 27, no. 4
p. 109569

Abstract

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Summary: 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 in vitro. 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.

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