Establishment of Trophoblast‐Like Tissue Model from Human Pluripotent Stem Cells in Three‐Dimensional Culture System

The placenta has a lifelong impact on the health of both the mother and fetus. Despite its significance, human early placental development is poorly understood due to the limited models. The models that can reflect the key features of early human placental development, especially at early gestation, are still lacking. Here, the authors report the generation of trophoblast‐like tissue model from human pluripotent stem cells (hPSCs) in three‐dimensional (3D) cultures. hPSCs efficiently self‐organize into blastocoel‐like cavities under defined conditions, which produce different trophoblast subtypes, including cytotrophoblasts (CTBs), syncytiotrophoblasts (STBs), and invasive extravillous trophoblasts (EVTs). The 3D cultures can exhibit microvilli structure and secrete human placenta‐specific hormone. Single‐cell RNA sequencing analysis further identifies the presence of major cell types of trophoblast‐like tissue as existing in vivo. The results reveal the feasibility to establish 3D trophoblast‐like tissue model from hPSCs in vitro, which is not obtained by monolayer culture. This new model system can not only facilitate to dissect the underlying mechanisms of early human placental development, but also imply its potential for study in developmental biology and gestational disorders.