Cripto is essential to capture mouse epiblast stem cell and human embryonic stem cell pluripotency

Nat Commun. 2016 Sep 2:7:12589. doi: 10.1038/ncomms12589.


Known molecular determinants of developmental plasticity are mainly transcription factors, while the extrinsic regulation of this process has been largely unexplored. Here we identify Cripto as one of the earliest epiblast markers and a key extracellular determinant of the naive and primed pluripotent states. We demonstrate that Cripto sustains mouse embryonic stem cell (ESC) self-renewal by modulating Wnt/β-catenin, whereas it maintains mouse epiblast stem cell (EpiSC) and human ESC pluripotency through Nodal/Smad2. Moreover, we provide unprecedented evidence that Cripto controls the metabolic reprogramming in ESCs to EpiSC transition. Remarkably, Cripto deficiency attenuates ESC lineage restriction in vitro and in vivo, and permits ESC transdifferentiation into trophectoderm lineage, suggesting that Cripto has earlier functions than previously recognized. All together, our studies provide novel insights into the current model of mammalian pluripotency and contribute to the understanding of the extrinsic regulation of the first cell lineage decision in the embryo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cellular Reprogramming / genetics
  • Embryonic Development / physiology*
  • Embryonic Stem Cells / physiology*
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / metabolism*
  • Germ Layers / cytology
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nodal Protein / metabolism
  • Pluripotent Stem Cells / physiology*
  • Smad2 Protein / metabolism
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism*


  • CTNNB1 protein, mouse
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • Nodal Protein
  • Nodal protein, mouse
  • Smad2 Protein
  • Smad2 protein, mouse
  • Tdgf1 protein, mouse
  • Wnt Proteins
  • beta Catenin
  • Epidermal Growth Factor