Stem-cell-derived trophoblast organoids model human placental development and susceptibility to emerging pathogens

Trophoblast organoids derived from placental villi provide a 3D model system of human placental development, but access to first-trimester tissues is limited. Here, we report that trophoblast stem cells isolated from naive human pluripotent stem cells (hPSCs) can efficiently self-organize into 3D stem-cell-derived trophoblast organoids (SC-TOs) with a villous architecture similar to primary trophoblast organoids. Single-cell transcriptome analysis reveals the presence of distinct cytotrophoblast and syncytiotrophoblast clusters and a small cluster of extravillous trophoblasts, which closely correspond to trophoblast identities in the post-implantation embryo. These organoid cultures display clonal X chromosome inactivation patterns previously described in the human placenta. We further demonstrate that SC-TOs exhibit selective vulnerability to emerging pathogens (SARS-CoV-2 and Zika virus), which correlates with expression levels of their respective entry factors. The generation of trophoblast organoids from naive hPSCs provides an accessible 3D model system of the developing placenta and its susceptibility to emerging pathogens. [Display omitted] •Single-cell analysis of human stem-cell-derived trophoblast organoids (SC-TOs)•SC-TO subpopulations correspond to trophoblast cell types in human embryos•SC-TOs recapitulate placental X chromosome inactivation dynamics•SC-TOs model selective placental vulnerability to emerging viral infections Theunissen et al. describe a methodology for deriving self-renewing 3D trophoblast organoids from naive human pluripotent stem cells. They demonstrate that stem-cell-derived trophoblast organoids model human placental development, X chromosome inactivation, and placental susceptibility to infection by emerging viral pathogens (SARS-CoV-2 and Zika virus).