NANOG and CDX2 pattern distinct subtypes of human mesoderm during exit from pluripotency

Cell Stem Cell. 2014 Sep 4;15(3):310-325. doi: 10.1016/j.stem.2014.06.006. Epub 2014 Jul 18.


Mesoderm is induced at the primitive streak (PS) and patterns subsequently into mesodermal subtypes and organ precursors. It is unclear whether mesoderm induction generates a multipotent PS progenitor or several distinct ones with restricted subtype potentials. We induced mesoderm in human pluripotent stem cells with ACTIVIN and BMP or with GSK3-β inhibition. Both approaches induced BRACHYURY(+) mesoderm of distinct PS-like identities, which had differing patterning potential. ACTIVIN and BMP-induced mesoderm patterned into cardiac but not somitic subtypes. Conversely, PS precursors induced by GSK3-β inhibition did not generate lateral plate and cardiac mesoderm and favored instead somitic differentiation. The mechanism of these cell fate decisions involved mutual repression of NANOG and CDX2. Although NANOG was required for cardiac specification but blocked somitic subtypes, CDX2 was required for somitic mesoderm but blocked cardiac differentiation. In sum, rather than forming a common PS progenitor, separate induction mechanisms distinguish human mesoderm subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism
  • Body Patterning
  • Bone Morphogenetic Proteins / metabolism
  • CDX2 Transcription Factor
  • Cell Line
  • Cell Lineage
  • Fetal Proteins / metabolism
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Homeodomain Proteins / metabolism*
  • Humans
  • Mesoderm / cytology
  • Mesoderm / embryology*
  • Mesoderm / metabolism*
  • Myocardium / cytology
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / metabolism
  • Nanog Homeobox Protein
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / metabolism*
  • Primitive Streak / cytology
  • Regulatory Sequences, Nucleic Acid / genetics
  • Signal Transduction
  • T-Box Domain Proteins / metabolism


  • Bone Morphogenetic Proteins
  • CDX2 Transcription Factor
  • CDX2 protein, human
  • Fetal Proteins
  • Homeodomain Proteins
  • NANOG protein, human
  • Nanog Homeobox Protein
  • T-Box Domain Proteins
  • Activins
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • Brachyury protein