A novel in vitro stem cell model to study maternal endothelial function in preeclampsia

Maternal endothelium dysfunction is a central component to preeclampsia pathogenesis. Studies to dissect the maternal endothelial dysfunction, particularly on a patient-specific basis, is hampered by access to systemic primary arterial endothelial cells (ECs). The aim of this study was to establish a replenishable patient-specific in vitro maternal ECs model to allow robust mechanistic studies to dissect preeclampsia endothelial dysfunction. Induced pluripotent stem cells (iPSCs) derived from three women were differentiated into ECs using our recently developed protocol. The differentiated ECs were exposed to pooled banked sera from normotensive pregnancies (n=24), preeclamptic pregnancies (n=26), normotensive postpartum for non-pregnant comparison (n=22) and controls [basal media and fetal bovine serum (FBS) as a positive control]. ECs functional analyses (nitric oxide release, migration, and tube formation) were evaluated in triplicate/quadruplicate for all 3 lines. Multiple group comparisons were performed by one-way ANOVAs followed by Tukey tests. Significance was considered as P < 0.05. Patient-specific iPSCs were established and subsequently differentiated into ECs (Fig. 1). Levels of nitric oxide release were significantly lower after incubation with preeclamptic sera compared to the FBS control, and normotensive and non-pregnant (postpartum) sera treatments were also lower than FBS but higher than PE treatments (Fig. 2A). Tube formation and migration also demonstrated significantly impaired functions by preeclamptic sera compared to FBS controls (Fig. 2B and 2C). Cell viabilities were not affected by sera treatment (Fig. 2D). Similar results were obtained for all three patient-specific lines. Establishment of patient-derived iPSCs-ECs treated with pregnancy sera serves as a novel model to study maternal endothelial dysfunction. This system makes it possible to define the interplay between individual maternal endothelial health and the circulating factors that lead to preeclampsia endothelial dysfunction.View Large Image Figure ViewerDownload Hi-res image Download (PPT)