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Retrovirus\u2010derived fusogenic proteins, known as syncytins, regulate trophoblast fusion by interacting with specific receptors. In humans, two syncytins, Syncytin\u20101 (Syn1) and Syncytin\u20102 (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 <jats:italic>Syn1<\/jats:italic> and <jats:italic>Syn2<\/jats:italic> knockout (KO) human trophoblast stem cells (hTSCs). ST differentiation assays revealed that Syn2 plays a predominant role in trophoblast\u2010trophoblast 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\u2010trophoblast fusion, Syn1 plays a predominant role in trophoblast\u2010EMSC fusion. Given that fusion\u2010capable 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\u2010trophoblast fusion.<\/jats:p>","DOI":"10.1111\/dgd.70014","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T06:46:17Z","timestamp":1749797177000},"page":"270-278","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Syncytin\u20101 Is Responsible for the Fusion Between Human Trophoblasts and Endometrial Stromal Cells"],"prefix":"10.1111","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4098-9472","authenticated-orcid":false,"given":"Akira","family":"Oike","sequence":"first","affiliation":[{"name":"Department of Trophoblast Research Institute of Molecular Embryology and Genetics, Kumamoto University  Kumamoto 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