CTNND1 affects trophoblast proliferation and specification during human embryo implantation

Abstract The placenta, serving as the crucial link between maternal and infant, plays a pivotal role in maintaining a healthy pregnancy. Placental dysplasia can lead to various complications, underscoring the importance of understanding trophoblast lineage development. During peri-implantation, the trophectoderm (TE) undergoes differentiation into cytotrophoblast (CTB), syncytiotrophoblast (STB), and extravillous trophoblast (EVT). However, the specification and regulation of human trophoblast lineage during embryo implantation, particularly in the peri-implantation phase, remain to be explored. In this study, we employed a co-culture model of human endometrial cells and native embryos and analyzed the single-cell transcriptomic data of 491 human embryonic trophoblasts during E6 to E10 to identify the key regulatory factors and the lineage differentiation process during peri-implantation. Our data identified four cell subpopulations during the implantation, including a specific transitional state toward the differentiation in which the CTNND1, one crucial component of Wnt signaling pathway activated by cadherins, acted as a crucial factor. Knockdown of CTNND1 impacted the proliferative capacity of trophoblast stem cells (hTSCs), leading to early EVT-like differentiation. Intriguingly, ablation of CTNND1 compromised the terminal differentiation of hTSCs toward both STB or EVT in vitro. Those observations identified the role of cell adhesion-mediated Wnt signaling in hTSC self-renewal, as well as suggest that this signaling pathway controls a transitional state that is crucial for trophoblast lineage specification. These findings contribute valuable insights into trophoblast lineage dynamics and offer a reference for research on placental-related diseases.