Sophia Mähr and Gudrun Valdimarsdottir
During human placental development, fetal trophoblasts undergo epithelial-to-mesenchymal transition (EMT) to invade the extracellular matrix towards maternal spiral arteries, followed by mesenchymal-to-endothelial transition (MEndT) to replace the endothelium and induce spiral artery remodeling for adequate placental perfusion. These processes seem to fail in the pregnancy-related disorder preeclampsia, however molecular mechanisms underlying both differentiation events remain elusive. The aim of the project was to elucidate the TGFβ signaling cascade as well as flow-induced shear stress as potential inducers of EMT in HTR8/SVneo trophoblast cells. To address this aim, the TGFβ signaling pathway and its effect on EMT marker expression as well as on cell migration have been studied in trophoblast cells. Further on, fluid shear stress experiments have been established to investigate the impact of different shear stress rates on the transition process at the maternal-fetal interface. We found that TGFβ signaled through distinct receptor complexes to initiate short-term SMAD1/5 and long-term SMAD2/3 phosphorylation, leading to increased EMT marker expression. However, TGFβ did inhibit trophoblast migration, indicating that additional regulators are required to induce migration characteristic for EMT. The specific flow-induced shear stress of 0.05 dyn/cm2 led to EMT marker upregulation, suggesting that blood flow-derived mechanical cues contribute to the differentiation process in trophoblast cells. These studies characterize the TGFβ signaling pathway as well as flow-induced shear stress as potential regulators of prenatal EMT, providing further insights into upstream mechanisms and possible targets for future research in the field of human placental development and preeclampsia.
