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.

Automated summary

This study reports the formation of 3D trophoblast organoids derived from naive human pluripotent stem cells. These organoids exhibit a villous architecture similar to primary trophoblast organoids and display distinct trophoblast cell types. Importantly, they also show selective vulnerability to emerging pathogens such as SARS-CoV-2 and Zika virus. This research provides an accessible model system for studying placental development and its susceptibility to emerging pathogens.