Naive Human Embryonic Stem Cells Can Give Rise to Cells with a Trophoblast-like Transcriptome and Methylome

Human embryonic stem cells (hESCs) readily differentiate to somatic or germ lineages but have impaired ability to form extra-embryonic lineages such as placenta or yolk sac. Here, we demonstrate that naive hESCs can be converted into cells that exhibit the cellular and molecular phenotypes of human trophoblast stem cells (hTSCs) derived from human placenta or blastocyst. The resulting “transdifferentiated” hTSCs show reactivation of core placental genes, acquisition of a placenta-like methylome, and the ability to differentiate to extravillous trophoblasts and syncytiotrophoblasts. Modest differences are observed between transdifferentiated and placental hTSCs, most notably in the expression of certain imprinted loci. These results suggest that naive hESCs can differentiate to extra-embryonic lineage and demonstrate a new way of modeling human trophoblast specification and placental methylome establishment. [Display omitted] •Naive hESCs can be transdifferentiated to hTSC-like cells and purified by FACS•Transdifferentiated hTSCs (tdhTSCs) are similar to hTSCs from placenta•tdhTSCs have placenta-like methylome•Modest methylation abnormalities are observed in tdhTSCs Cinkornpumin and colleagues provide a protocol for converting naive human embryonic stem cells (hESCs) into transdifferentiated trophoblast stem cells (tdhTSCs). The resulting tdhTSCs show gene expression and differentiation capabilities akin to hTSCs from placenta or blastocyst. They also have a placenta-like methylome, although there are residual traces of hESC-methylation pattern.