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

doi:10.1016/j.isci.2024.109569

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

iScience. 2024 Mar 25;27(4):109569. doi: 10.1016/j.isci.2024.109569. eCollection 2024 Apr 19.

Authors

Robert Morey^{1

2

3}, Tony Bui^{1

2

3}, Virginia Chu Cheung^{1

2

3}, Chen Dong⁴, Joseph E Zemke⁴, Daniela Requena^{1

2

3}, Harneet Arora^{1

2

3}, Madeline G Jackson^{1

2

3}, Donald Pizzo¹, Thorold W Theunissen⁴, Mariko Horii^{1

2

3}

Affiliations

¹ Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA.
² Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92093, USA.
³ Center for Perinatal Discovery, University of California San Diego, La Jolla, CA 92093, USA.
⁴ Department of Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

Abstract

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.

Keywords: Cell biology; Molecular biology; Omics; Transcriptomics.

Abstract

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