Progression from naive to primed pluripotency. (a) Progression of epiblast development in the mouse embryo and corresponding conceptual pluripotent stages. The mature blastocyst comprises three cell lineages: naive epiblast (dark blue), PrE (green) and trophoblast (grey). By E6.5 lineage priming has commenced. Ectoderm, blue; mesoderm, red; definitive endoderm, orange; germline, brown (adapted from Najm et al. [8]). (b) Progression of naive ESCs to a lineage primed state upon 2i withdrawal. Rex1 is asynchronously downregulated and exit from the naive state is marked with loss of Rex1. These Rex1-negative cells might resemble the early postimplantation epiblast, the intermediate formative stage from which lineage-specified cells emerge. (c) Expression periods of naive, early postimplantation and priming factors together with Oct4 and Sox2 during pluripotency transitions.