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

Abstract

Throughout evolution, the placenta has diversified in structure and cellular composition while maintaining its essential role in supporting fetal development. Trophoblasts, key cells responsible for nutrient exchange and immune modulation, are a conserved feature of all placentas. Although primate placentas share broad morphological similarities, species-specific differences in gene expression remain poorly characterized, largely due to the lack of tractable in vitro models. To address this gap, we developed rhesus macaque placental organoids representing both trophoblast and maternal-derived decidual cell types and compared them with human placental organoids. Using integrated single-cell and single-nucleus RNA sequencing, we identified both shared and species-specific transcriptional programs across corresponding trophoblast lineages. We further reconstructed lineage trajectories leading to multinucleated syncytiotrophoblast and invasive extravillous trophoblast populations, revealing conserved differentiation pathways alongside divergent gene expression signatures. This work establishes new in vitro models of the nonhuman primate placenta and defines the molecular distinctions between human and rhesus trophoblasts, offering insights into the evolutionary adaptations underlying placental development.