Spatio-temporal expression of E-cadherin mediates trophoblast lineage transitions during human placentation

Abstract Human placentation relies on the precise differentiation of embryo-derived trophoblasts into specialized lineages, a process strictly regulated by the spatio-temporal expression of key genes. Herein, we report that the expression of the transmembrane glycoprotein, known as E-cadherin, fluctuates dynamically across distinct trophoblast subpopulations rather than acting as a static structural tether. Along the villous pathway, E-cadherin expression initially increases to facilitate the aggregation of cytotrophoblast cells (CTs) and is subsequently downregulated via transcriptional repression, enzymatic cleavage and physical compressive forces for the CTs to fuse into the syncytiotrophoblast lineage. Conversely, along the extravillous pathway, its transient downregulation characterizes an epithelial-to-mesenchymal transition that permits trophoblast invasion into the decidua, followed by its upregulation in the endovascular trophoblasts to potentially facilitate vascular adhesion and spiral artery remodeling. Dysregulation of this expression pattern of E-cadherin is evident in the placenta of pregnancies complicated by preeclampsia or fetal growth restriction. To advance the field, future research must transition from descriptive profiling to functional mechanisms by defining the precise intracellular degradation pathways of E-cadherin in trophoblast lineages and then clarify whether the upstream regulators operate in linear or parallel networks. Utilizing advanced biophysical tools and spatial transcriptomics will help clarify how tissue stiffness, fluid shear stress, and local immune cells mechanically and immunologically trigger this E-cadherin switch via mechanosensitive channels. Translational studies should explore the feasibility of using circulating soluble E-cadherin fragments in maternal blood as an early biomarker of defective placentation.