Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation

Sci Rep. 2016 Jul 19;6:29868. doi: 10.1038/srep29868.


Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor β (TGF-β)-induced epithelial-mesenchymal transition. In addition to TGF-β receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked α-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-β-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-β-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics*
  • Collagen / metabolism
  • Embryonic Development / genetics
  • Epithelial Cells / drug effects
  • Epithelial-Mesenchymal Transition / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Developmental / drug effects
  • Humans
  • Keratinocytes / drug effects
  • Liver X Receptors / agonists
  • Liver X Receptors / genetics*
  • Mice
  • Myofibroblasts / cytology*
  • Receptors, Transforming Growth Factor beta
  • Signal Transduction / drug effects
  • Small Molecule Libraries / pharmacology
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / genetics


  • Liver X Receptors
  • Receptors, Transforming Growth Factor beta
  • Small Molecule Libraries
  • Transforming Growth Factor beta
  • Collagen