Culturing Cytotrophoblasts Reverses Gene Dysregulation in Preeclampsia Revealing Possible Causes

During human pregnancy, a subset of placental cytotrophoblasts (CTBs) differentiates into cells that aggressively invade the uterus and its vasculature, anchoring the progeny and rerouting maternal blood to the placenta. In preeclampsia (PE), CTB invasion is limited, reducing placental perfusion and/or creating intermittent flow. This syndrome, affecting 4-8% of pregnancies, entails maternal vascular alterations (e.g., high blood pressure, proteinuria, and edema) fetal growth restriction. The only cure is removal of the faulty placenta, i.e., delivery. Previously we showed that defective CTB differentiation contributes to the placental component of PE, but the causes were unknown. Here, CTBs isolated from PE and control placentas were cultured for 48 h, enabling differentiation/invasion. In various severe forms of PE, transcriptomics revealed common aberrations in CTB gene expression immediately after isolation that resolved in culture. The upregulated genes included SEMA3B. Adding this protein to normal CTBs inhibited invasion and re-created aspects of the phenotype of these cells in PE. Additionally, SEMA3B downregulated VEGF signaling through the PI3K/AKT and GSK3 pathways, effects that were observed in PE CTBs. We propose that, in severe PE, the in vivo environment dysregulates CTB gene expression, the autocrine actions of the upregulated molecules, including SEMA3B, impair differentiation/invasion/signaling and patient-specific factors determine the signs.

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Zhou Y, Gormley MJ, Hunkapiller NM, Kapidzic M, Stolyarov Y, Feng V, Nishida M, Drake PM, Bianco K, Wang F, McMaster MT, Fisher SJ