Abstract

Early Onset Preeclampsia (EOPE) in a Model For Early Stage Human Placental Trophoblast

Toshihiko Ezashi, Research Associate Professor, The University of Missouri

We have established a model for early onset preeclampsia (EOPE) that uses induced pluripotent stem cells (iPSC) generated from umbilical cords of infants born to mothers who experienced EOPE. These iPSC lines were converted to placental trophoblast (TB), thus recapitulating early stage aspects of the pregnancies they represented. Eight control (CTL) iPSC-TB and 14 EOPE iPSC-TB were tested to assess their abilities to invade through Matrigel. Under 5 % O2, CTL-TB and EOPE-TB lines did not differ, but, under the more stressful 20 % O2 conditions, invasiveness was lower in EOPE-TB than in CTL-TB (P = 0.024). Although invasiveness of CTL-TB was not influenced by 20 % O2, that of EOPE-TB was markedly reduced (P = 0.008) compared to 5% O2. Placental growth factor (PGF) production also decreased (P < 0.05) in EOPE cultures under 20 % O2. RNAseq analysis revealed only two differentially expressed genes (RPS17, FDR = 0.0005; MTRNR2L2, FDR = 0.005) significantly down-regulated in EOPE-TB under 20 % O2. A weighted correlation network analysis (WGCNA), revealed ten gene modules in CTL lines, three of which were correlated with TB invasion. Of these three, two were also linked to O2 responsiveness and were enriched in ontology terms related to cell migration and angiogenesis. Of the four gene modules identified in EOPE-TB, none were correlated with invasion, and two were correlated with O2 responsiveness. These results indicate that, under high O2 and possibly other stressful conditions, invasion by EOPE-TB becomes dysregulated, which helps to reveal the underlying pathology of shallow invasion of TB in the EOPE placenta. The results also indicate the value of the iPSC approach to studying EOPE.