Concomitant inhibition of prolyl hydroxylases and ROCK initiates differentiation of mesenchymal stem cells and PC12 towards the neuronal lineage

Biochem Biophys Res Commun. 2008 Dec 12;377(2):400-406. doi: 10.1016/j.bbrc.2008.09.145. Epub 2008 Oct 9.


This study demonstrates that a prolyl hydroxylase inhibitor, FG-0041, is able, in combination with the ROCK inhibitor, Y-27632, to initiate differentiation of mesenchymal stem cells (MSCs) into neuron-like cells. FG-0041/Y-27632 co-treatment provokes morphological changes into neuron-like cells, increases neuronal marker expression and provokes modifications of cell cycle-related gene expression consistent with a cell cycle arrest of MSC, three events showing the engagement of MSC towards the neuronal lineage. Moreover, as we observed in our previous studies with cobalt chloride and desferroxamine, the activation of HIF-1 by this prolyl hydroxylase inhibitor is potentiated by Y-27632 which could explain at least in part the effect of this co-treatment on MSC neuronal differentiation. In addition, we show that this co-treatment enhances neurite outgrowth and tyrosine hydroxylase expression in PC12 cells. Altogether, these results evidence that concomitant inhibition of prolyl hydroxylases and ROCK represents a relevant protocol to initiate neuronal differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / pharmacology
  • Animals
  • Cell Differentiation* / genetics
  • Cell Lineage
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation
  • Hypoxia-Inducible Factor 1 / metabolism
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / enzymology
  • Neurites / enzymology
  • Neurites / physiology
  • Neurons / cytology*
  • Neurons / enzymology
  • PC12 Cells
  • Phenanthrolines / pharmacology*
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors*
  • Pyridines / pharmacology
  • Rats
  • rho-Associated Kinases / antagonists & inhibitors*


  • Amides
  • Enzyme Inhibitors
  • FG 0041
  • Hypoxia-Inducible Factor 1
  • Phenanthrolines
  • Pyridines
  • Y 27632
  • Procollagen-Proline Dioxygenase
  • rho-Associated Kinases