RT Journal Article SR Electronic T1 Human Naïve Epiblast Cells Possess Unrestricted Lineage Potential JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.02.04.933812 DO 10.1101/2020.02.04.933812 A1 Ge Guo A1 Giuliano Giuseppe Stirparo A1 Stanley Strawbridge A1 Daniel Spindlow A1 Jian Yang A1 James Clarke A1 Anish Dattani A1 Ayaka Yanagida A1 Meng Amy Li A1 Sam Myers A1 Buse Nurten Özel A1 Jennifer Nichols A1 Austin Smith YR 2020 UL http://biorxiv.org/content/early/2020/10/07/2020.02.04.933812.abstract AB Classical mouse embryology has established a paradigm of early development driven by sequential lineage bifurcations. Accordingly, mouse embryonic stem cells derived from early epiblast have lost the potency to produce extraembryonic trophectoderm. We show in contrast that human naïve epiblast cells readily make trophectoderm. Inhibition of ERK signalling, instrumental in naïve stem cell propagation, unexpectedly potentiates trophectoderm formation, an effect enhanced by Nodal inhibition. Transcriptome analyses authenticate conversion into trophectoderm with subsequent production of syncitiotrophoblast, cytotrophoblast and trophoblast stem cells. Genetic perturbations indicate that NANOG suppresses and TFAP2C enables trophectoderm induction. Consistent with post-implantation progression, trophectoderm potential is extinguished in conventional human pluripotent stem cells, which instead make amnion. Finally, human embryo epiblasts from late blastocysts efficiently generate trophectoderm and differentiated trophoblast. Thus, pluripotent cells in the human embryo retain extraembryonic lineage plasticity and regenerative potential until implantation. Harnessing this unanticipated regulative capacity may be beneficial for assisted reproduction technology.Competing Interest StatementAS and GG are inventors on a patent application relating to human naive stem cells filed by the University of Cambridge.