Reelin regulates the migration and differentiation of extravillous trophoblastic cells

ApoER2/LRP8 is a receptor highly expressed in the placenta; however, its physiological role in this organ remains poorly understood. The VLDL receptor has been less studied in the placenta. Reelin, a relevant ligand for both receptors, is an extracellular glycoprotein that participates in neuronal polarization, migration and differentiation, hence having a central role in the central nervous system (CNS) development. Reelin triggers a complex signaling pathway that regulates cytoskeleton dynamics, cell migration, differentiation and gene expression. This paper aimed to determine whether the Reelin signaling pathway plays a role in cellular processes involved in placentation. Reelin receptors ApoER2 and VLDLR were found in first-trimester extravillous trophoblast (EVT) cell lines. EVT cells Swan 71 responded to Reelin exposure by activating PI3K-Akt and increasing ApoER2 protein levels, but not VLDLR. Additionally, a dual role for Reelin via PI3K was established in these cells, as it enhanced trophoblastic migration at 2% O2 (to mimic the hypoxic physiologic conditions of trophoblastic migration) and promoted differentiation to an endothelial-like phenotype at 21% O2. Migration was also stimulated, independent of PI3K, when cells were exposed to normoxic (21% O2) or chemically induced hypoxic (CoCl2) conditions. We propose that, physiologically, during the first trimester, Reelin, together with its receptors, could stimulate trophoblastic migration and differentiation. Interestingly, under hypoxia, ApoER2 and VLDLR protein levels were increased, and Reelin modulated hypoxia-inducible factor HIF1-α levels. ApoER2, VLDLR and Reelin were detected in human term placentas from normal and pre-eclampsia with severe features (PE-SF) pregnancies. In the plasma of first-trimester pregnant women, Reelin levels were lower in patients with severe preeclampsia (PE) at a time before the onset of PE clinical symptoms. Reelin could be involved in placentation, playing roles in EVT migration and differentiation. The reduction in maternal Reelin levels detected early in pregnancy could be a potential biomarker for PE.