iPSC-based modeling of preeclampsia identifies defects in extravillous trophoblast differentiation
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 previously been modeled in vitro. We previously derived induced pluripotent stem cells (iPSC) 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, then derived trophoblast stem cells (TSC) 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 promotor 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 the PE pathogenesis. Overall design: To investigate the mechanisms underlying preeclampsia (PE) we used iPSC derived from the placentas of three PE patients (1932, 1933, 1981) and three control patients (1754, 1938, 1947), converted these primed iPSC to naive iPSC and then differentiated the primed and naive iPSC lines to  trophoblast stem cells (TSC) and extravillous trophoblast (EVT).  We then performed gene expression profiling on all of  these samples using RNA-seq. For each timepoint and patient, we sequenced 3 replicates.