Distinct Molecular Trajectories Converge to Induce Naive Pluripotency

Understanding how cell identity transitions occur and whether there are multiple paths between the same beginning and end states are questions of wide interest. Here we show that acquisition of naive pluripotency can follow transcriptionally and mechanistically distinct routes. Starting from post-implantation epiblast stem cells (EpiSCs), one route advances through a mesodermal state prior to naive pluripotency induction, whereas another transiently resembles the early inner cell mass and correspondingly gains greater developmental potency. These routes utilize distinct signaling networks and transcription factors but subsequently converge on the same naive endpoint, showing surprising flexibility in mechanisms underlying identity transitions and suggesting that naive pluripotency is a multidimensional attractor state. These route differences are reconciled by precise expression of Oct4 as a unifying, essential, and sufficient feature. We propose that fine-tuned regulation of this “transition factor” underpins multidimensional access to naive pluripotency, offering a conceptual framework for understanding cell identity transitions. [Display omitted] •Reprogramming routes differ transcriptionally and mechanistically•Reprogramming intermediates resemble different developmental stages•Distinct routes converge on precise Oct4 regulation to permit identity transition•Precise Oct4 expression is sufficient for reprogramming of EpiSCs and fibroblasts Stuart et al. report distinct routes of reprogramming to naive pluripotency. These differ in their transcriptional trajectories, mechanistic requirements, and developmental parallels, thus demonstrating considerable flexibility for a given cell identity transition to occur. Distinct routes converge on precise Oct4 expression, which is necessary and sufficient for naive pluripotency induction.