Distinct Molecular Trajectories Converge to Induce Naive Pluripotency

Hannah T Stuart, Giuliano G Stirparo, Tim Lohoff, Lawrence E Bates, Masaki Kinoshita, Chee Y Lim, Elsa J Sousa, Katsiaryna Maskalenka, Aliaksandra Radzisheuskaya, Andrew A Malcolm, Mariana R P Alves, Rebecca L Lloyd, Sonia Nestorowa, Peter Humphreys, William Mansfield, Wolf Reik, Paul Bertone, Jennifer Nichols, Berthold Göttgens, José C R Silva*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)388-406.e8
JournalCell Stem Cell
Volume25
Issue number3
Early online date15 Aug 2019
DOIs
Publication statusPublished - 5 Sept 2019

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Blastocyst Inner Cell Mass/physiology
  • Cell Differentiation
  • Cell Line
  • Cell Plasticity
  • Cellular Reprogramming
  • Female
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Germ Layers/physiology
  • Mice
  • Mice, Inbred C57BL
  • Octamer Transcription Factor-3/genetics
  • Pluripotent Stem Cells/physiology
  • Signal Transduction

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