Syncytin‐1 Is Responsible for the Fusion Between Human Trophoblasts and Endometrial Stromal Cells

ABSTRACT Syncytiotrophoblasts (STs) are multinucleated cells formed by the fusion of trophoblasts and play critical roles in placental development and function. Retrovirus‐derived fusogenic proteins, known as syncytins, regulate trophoblast fusion by interacting with specific receptors. In humans, two syncytins, Syncytin‐1 (Syn1) and Syncytin‐2 (Syn2), have been identified. Although both are considered to be involved in ST formation, the expression patterns of Syn1, Syn2, and their receptors differ significantly, suggesting that Syn1 and Syn2 may have distinct roles. To investigate the functional differences of syncytins in human trophoblasts, we generated Syn1 and Syn2 knockout (KO) human trophoblast stem cells (hTSCs). ST differentiation assays revealed that Syn2 plays a predominant role in trophoblast‐trophoblast fusion. We also examined the fusion between hTSCs and endometrial stromal cells (EMSCs), as trophoblasts and EMSCs interact directly during implantation, and genes encoding Syn1 and Syn2 receptors are expressed in EMSCs. This analysis revealed that hTSCs do fuse with EMSCs, and in contrast to trophoblast‐trophoblast fusion, Syn1 plays a predominant role in trophoblast‐EMSC fusion. Given that fusion‐capable Syn1 is found only in primates whose embryos invade deep into the uterus, we hypothesize that Syn1 may be more involved in implantation rather than in trophoblast‐trophoblast fusion.