Comparative analysis of rhesus macaque and human placental organoids highlights evolutionary differences in placentation.

Throughout evolution, the placenta has diversified in both structure and cellular composition while maintaining its fundamental function. Trophoblasts are fetal-derived cells responsible for nourishing and protecting the developing fetus and are a universal component of all placentas. While primate placentas exhibit many shared morphological features, species-specific differences in gene expression remain largely unexplored, primarily due to the lack of suitable in vitro models. To address this gap, we developed organoids from rhesus macaque placentas, including trophoblast and maternal-derived decidua types, and compared them with organoids derived from human placentas. We performed comparative single-cell RNA sequencing to delineate shared and distinct transcriptional signatures between rhesus macaque and human trophoblasts. We further defined the differentiation trajectories leading to the multinucleated syncytiotrophoblast, highlighting both shared and unique transcriptional signatures between rhesus macaque and human placentas. This work establishes novel in vitro models of the non-human primate placenta and characterizes distinct trophoblast gene profiles in rhesus macaques and humans, providing insights into interspecies variations in placental biology.