Crosstalk between HIF-1 and ROCK pathways in neuronal differentiation of mesenchymal stem cells, neurospheres and in PC12 neurite outgrowth.
This study demonstrates that the Rho-kinase (ROCK) inhibitor, Y-27632, potentiates not only the effect of cobalt chloride (CoCl(2)) but also that of deferoxamine, another HIF-1 inducer, on mesenchymal stem cell (MSC) neuronal differentiation. HIF-1 is essential for CoCl(2)+/-Y-27632-induced MSC neuronal differentiation, since agents inhibiting HIF-1 abolish the changes of morphology and cell cycle arrest-related gene or protein expressions (p21, cyclin D1) and the increase of neuronal marker expressions (Tuj1, NSE). Y-27632 potentiates the CoCl(2)-induced decrease of cyclin D1 and nestin expressions, the increase of HIF-1 activation and EPO expression, and decreases pVHL expression. Interestingly, CoCl(2) decreases RhoA expression, an effect potentiated by Y-27632, revealing crosstalk between HIF-1 and RhoA/ROCK pathways. Moreover, we demonstrate a synergistic effect of CoCl(2) and Y-27632 on neurosphere differentiation into neurons and PC12 neurite outgrowth underlining that a co-treatment targeting both HIF-1 and ROCK pathways might be relevant to differentiate stem cells into neurons.
Pacary
Emilie
E
UMR-CNRS 6185, Hypoxia and Cerebrovascular Physiopathology Group, University of Caen, CYCERON, Bd Henri Becquerel, BP 5229, F-14074 Caen cedex, France.
Tixier
Emmanuelle
E
Coulet
Florence
F
Roussel
Simon
S
Petit
Edwige
E
Bernaudin
Myriam
M
D000577:Amides / Q000494:pharmacology; D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D054460:rho-Associated Kinases
D000577:Amides; D016587:Antimutagenic Agents; D004791:Enzyme Inhibitors; D051793:Hypoxia-Inducible Factor 1; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011725:Pyridines; C108830:Y 27632; D003035:Cobalt; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C018021:cobaltous chloride