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
Affiliations
Robert Morey
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; Center for Perinatal Discovery, University of California San Diego, La Jolla, CA 92093, USA
Tony Bui
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; Center for Perinatal Discovery, University of California San Diego, La Jolla, CA 92093, USA
Virginia Chu Cheung
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; Center for Perinatal Discovery, University of California San Diego, La Jolla, CA 92093, USA
Chen Dong
Department of Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Joseph E. Zemke
Department of Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Daniela Requena
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; Center for Perinatal Discovery, University of California San Diego, La Jolla, CA 92093, USA
Harneet Arora
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; Center for Perinatal Discovery, University of California San Diego, La Jolla, CA 92093, USA
Madeline G. Jackson
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; Center for Perinatal Discovery, University of California San Diego, La Jolla, CA 92093, USA
Donald Pizzo
Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA
Thorold W. Theunissen
Department of Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Mariko Horii
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; Center for Perinatal Discovery, University of California San Diego, La Jolla, CA 92093, USA; Corresponding author
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.
