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Cell Stem Cell. 2019 Sep 5;25(3):388-406.e8. doi: 10.1016/j.stem.2019.07.009. Epub 2019 Aug 15.

Distinct Molecular Trajectories Converge to Induce Naive Pluripotency.

Author information

1
Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Biochemistry, University of Cambridge, Cambridge, UK.
2
Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
3
Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
4
Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Haematology and Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
5
Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Babraham Institute and Wellcome Sanger Institute, Cambridge, UK.
6
Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Biochemistry, University of Cambridge, Cambridge, UK. Electronic address: jcs64@cam.ac.uk.

Abstract

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.

KEYWORDS:

cell identity transitions; pluripotency; reprogramming; signaling; transcriptional networks

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