Reelin regulates migration and differentiation of extravillous trophoblastic cells: Implications for Preeclampsia

Background ApoER2/LRP8 is a receptor highly expressed in the placenta; however, its physiological role in this organ is little known. Reelin, an ApoER2 ligand, is an extracellular glycoprotein that participates in neuronal polarization, migration and differentiation, hence having a central role in the central nervous system (CNS) development. Upon binding to ApoER2, Reelin triggers a complex signaling pathway that regulates cytoskeleton dynamics, gene expression and transcript translation. This paper aimed to determine whether the ApoER2/Reelin signaling pathway has roles in cellular processes related to placentation. Results We characterized the Reelin-ApoER2 system using first-trimester extravillous trophoblast (EVT) cell lines. The receptor is present at the cell surface and in the nucleus. EVT cells Swan 71 responded to Reelin exposure by activating the PI3K-Akt and increasing ApoER2 levels. Additionally, a dual role of Reelin through PI3K was established in these cells, as it enhanced trophoblastic migration at 2% O ₂ (to mimic the hypoxic physiologic conditions of trophoblastic migration) and its differentiation to an endothelial-like phenotype at 21% O ₂ . Migration was also stimulated, independent of PI3K, when cells were exposed to normoxic culture conditions (21% of O ₂ ) or chemically induced hypoxia (by CoCl ₂ ). We propose that physiologically, during the first trimester, Reelin, together with its ApoER2 receptor, could act by stimulating trophoblastic migration and differentiation. Interestingly, Reelin also modulated hypoxia-inducible factor HIF1-α levels. Both ApoER2 and Reelin were detected in human term placentas from normal and preeclampsia with severe features (PE-SF) pregnancies. Reelin plasma levels were lower in severe PE patients already in the first semester of pregnancy, before the appearance of PE symptoms. Conclusions Reelin could be involved in placentation, playing roles in EVT migration and differentiation. The reduction in maternal Reelin levels detected at early pregnancy could be a potential biomarker for PE.