Human Naïve Epiblast Cells Possess Unrestricted Lineage Potential

Classical mouse embryology has established a paradigm of early development drivenby sequential lineage bifurcations. Accordingly, mouse embryonic stem cells derivedfrom early epiblast have lost the potency to produce extraembryonic trophectoderm.We show in contrast that human naive epiblast cells readily make trophectoderm.Inhibition of ERK signalling, instrumental in naive stem cell propagation, unexpectedlypotentiates trophectoderm formation, an effect enhanced by Nodal inhibition.Transcriptome analyses authenticate conversion into trophectoderm with subsequentproduction of syncitiotrophoblast, cytotrophoblast and trophoblast stem cells. Geneticperturbations indicate that NANOG suppresses and TFAP2C enables trophectoderminduction. Consistent with post-implantation progression, trophectoderm potential isextinguished in conventional human pluripotent stem cells, which instead makeamnion. Finally, human embryo epiblasts from late blastocysts efficiently generatetrophectoderm and differentiated trophoblast. Thus, pluripotent cells in the humanembryo retain extraembryonic lineage plasticity and regenerative potential untilimplantation. Harnessing this unanticipated regulative capacity may be beneficial forassisted reproduction technology. Human naive pluripotent stem cells (HNES1) were differentiated to trophectoderm in N2B27 basal medium supplementated with PD0325902(PD03) and PD03+A1(PDA83). RNA samples were collected in a time course.