Retinoic acid and bone morphogenetic protein signaling synergize to efficiently direct epithelial differentiation of human embryonic stem cells

Stem Cells. 2008 Feb;26(2):372-80. doi: 10.1634/stemcells.2007-0501. Epub 2007 Oct 25.


Human embryonic stem cells (hESCs) can differentiate to various somatic lineages, including stratified squamous epithelia, although the molecular mechanisms of epithelial specification from hESCs currently remain undefined. Here, we demonstrate a novel, stage-specific effect of retinoic acid (RA) on epithelial differentiation of hESCs. RA strongly upregulated expression of keratin 18 and the transcription factor p63, which is involved in epidermal morphogenesis and ectodermal specification, while repressing early neural marker transcription. RA-induced hESCs efficiently differentiated to keratin 14-expressing epithelial cells, although this effect was dependent upon on the context of bone morphogenetic protein signaling. Furthermore, these hESC-derived keratinocytes could be subcultured to obtain relatively pure keratinocyte populations that retained the capacity to terminally differentiate. These findings suggest that RA plays an important role in epithelial differentiation of hESCs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bone Morphogenetic Proteins / metabolism*
  • Cell Differentiation / drug effects
  • Cell Line
  • Culture Media, Serum-Free
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / drug effects*
  • Embryonic Stem Cells / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression / drug effects
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / drug effects
  • Pluripotent Stem Cells / metabolism
  • Signal Transduction / drug effects
  • Spheroids, Cellular / cytology
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Tretinoin / pharmacology*


  • Bone Morphogenetic Proteins
  • Culture Media, Serum-Free
  • Tretinoin