With the development of the embryo, the totipotent blastomere undergoes the first lineage decision to the inner cell mass (ICM) and the trophectoderm (TE). The ICM forms the fetus while the TE forms the placenta, which is one of the unique organs in mammals serving as the interface between maternal and fetal bloodstreams. Proper trophoblast lineage differentiation is crucial for correct placental and fetal development, including the TE progenitor self-renewal and its differentiation toward mononuclear cytotrophoblast, which later either develops into invasive extravillous trophoblast, remodeling the uterine vascular, or fuses into multinuclear syncytiotrophoblast, secreting pregnancy-sustaining hormone. Aberrant differentiation and gene expression of trophoblast lineage is associated with severe pregnancy disorders and fetal growth restriction. This review focuses on the early differentiation and key regulatory factors of trophoblast lineage, which have been poorly elucidated. Meanwhile, the recent development of trophoblast stem cells, trophectoderm stem cells, and blastoids derived from pluripotent stem cells bring the accessible model to investigate the profound mystery of embryo implantation and placentation and were also summarized.

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