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 undergoes differentiation into cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast. 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 human trophoblast stem cells, leading to early extravillous trophoblast-like differentiation. Intriguingly, ablation of CTNND1 compromised the terminal differentiation of human trophoblast stem cells toward syncytiotrophoblast or extravillous trophoblast in vitro. These findings contribute valuable insights into trophoblast lineage dynamics and offer a reference for research on placental-related diseases.

Summary Sentence

Those observations identified the role of cell adhesion-mediated Wnt signaling in human trophoblast stem cell self-renewal, as well as suggest that this signaling pathway controls a transitional state that is crucial for trophoblast lineage specification.

Graphical Abstract