Cell fate roadmap of human primed-to-naive transition reveals preimplantation cell lineage signatures

Human naive pluripotent stem cells offer a unique window into early embryogenesis studies. Recent studies have reported several strategies to obtain cells in the naive state. However, cell fate transitions and the underlying mechanisms remain poorly understood. Here, by a dual fluorescent reporter system, we depict the cell fate dynamics from primed state toward naive pluripotency with ALPG activation followed by the activation of OCT4-distal enhancer. Integration of transcription profiles and the chromatin accessibility landscape reveals the appearance of primitive endoderm and trophectoderm signatures in the transitioning subpopulations, with the capacities for derivation of extra-embryonic endoderm and trophoblast stem cell lines, respectively. Furthermore, despite different fluorescent dynamics, all transitioning intermediates are capable of reaching the naive state with prolonged induction, showing their developmental plasticity and potential. Overall, our study describes a global cell roadmap toward naive pluripotency and provides hints for embryo modeling-related studies.