Rotational trophoblast organoids reveal biomechanical regulation of trophoblast differentiation

Human placental development is essential for pregnancy but remains mechanistically obscure because early post-implantation tissues are inaccessible. Here, we establish a rotational trophoblast organoid platform that recapitulates selected morphogenetic features shared with early trophoblast development, including spontaneous syncytiotrophoblast (STB) differentiation and progressive fusion of lacuna-like cavities. Integrated multi-omic analyses associate this architecture with a biomechanical balance between attenuated YAP activity and peripheral CREB activation, with GCM1 stabilizing trophoblast chromatin state and POLQ supporting genome maintenance in rapidly expanding progenitors. The organoids display autonomous endocrine activity, induce an endometrial epithelial state consistent with metabolic activation, and can generate extravillous trophoblasts that directionally engage endothelial networks. This platform provides a framework for studying placental morphogenesis and tissue interactions relevant to pregnancy complications.