Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells

Stem Cell Reports. 2015 May 12;4(5):939-52. doi: 10.1016/j.stemcr.2015.04.001. Epub 2015 Apr 30.


The differentiation of pluripotent stem cells to hepatocytes is well established, yet current methods suffer from several drawbacks. These include a lack of definition and reproducibility, which in part stems from continued reliance on recombinant growth factors. This has remained a stumbling block for the translation of the technology into industry and the clinic for reasons associated with cost and quality. We have devised a growth-factor-free protocol that relies on small molecules to differentiate human pluripotent stem cells toward a hepatic phenotype. The procedure can efficiently direct both human embryonic stem cells and induced pluripotent stem cells to hepatocyte-like cells. The final population of cells demonstrates marker expression at the transcriptional and protein levels, as well as key hepatic functions such as serum protein production, glycogen storage, and cytochrome P450 activity.

MeSH terms

  • Blood Proteins / metabolism
  • Cell Differentiation / drug effects*
  • Cells, Cultured
  • Dexamethasone / pharmacology
  • Dimethyl Sulfoxide / pharmacology
  • Glycogen / metabolism
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Hepatocytes / cytology*
  • Hepatocytes / metabolism
  • Humans
  • Microscopy, Fluorescence
  • Oligopeptides / pharmacology
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / drug effects*
  • Pluripotent Stem Cells / metabolism
  • Proto-Oncogene Proteins c-met / agonists
  • Proto-Oncogene Proteins c-met / metabolism
  • Small Molecule Libraries / pharmacology*


  • Blood Proteins
  • Oligopeptides
  • Small Molecule Libraries
  • Dexamethasone
  • Glycogen
  • N-hexanoic-Tyr-Ile-(6) aminohexanoic amide
  • Proto-Oncogene Proteins c-met
  • Glycogen Synthase Kinase 3
  • Dimethyl Sulfoxide