Synergistic effects of CoCl(2) and ROCK inhibition on mesenchymal stem cell differentiation into neuron-like cells.
Journal of Cell Science. 2006-06-06; 119(13): 2667-2678
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1. J Cell Sci. 2006 Jul 1;119(Pt 13):2667-78. Epub 2006 Jun 13.
Synergistic effects of CoCl(2) and ROCK inhibition on mesenchymal stem cell
differentiation into neuron-like cells.
Pacary E(1), Legros H, Valable S, Duchatelle P, Lecocq M, Petit E, Nicole O,
(1)UMR-CNRS 6185, Neurodegenerescence: models and therapeutic strategies,
University of Caen, CYCERON, Bd Henri Becquerel, BP 5229, 14074 Caen CEDEX,
Bone-marrow-derived mesenchymal stem cells (MSCs) constitute an interesting
cellular source to promote brain regeneration after neurodegenerative diseases.
Recently, several studies suggested that oxygen-dependent gene expression is of
crucial importance in governing the essential steps of neurogenesis such as cell
proliferation, survival and differentiation. In this context, we analysed the
effect of the HIF-1 (hypoxia inducible factor-1) activation-mimicking agent
CoCl(2) on MSCs. CoCl(2) treatment increased the expression of the
anti-proliferative gene BTG2/PC3 and decreased cyclin D1 expression. Expression
of HIF-1alpha and its target genes EPO, VEGF and p21 was also upregulated. These
changes were followed by inhibition of cell proliferation and morphological
changes resulting in neuron-like cells, which had increased neuronal marker
expression and responded to neurotransmitters. Echinomycin, a molecule inhibiting
HIF-1 DNA-binding activity, blocked the CoCl(2) effect on MSCs. Additionally, by
using Y-27632, we demonstrated that Rho kinase (ROCK) inhibition potentiated
CoCl(2)-induced MSC differentiation in particular into dopaminergic neuron-like
cells as attested by its effect on tyrosine hydroxylase expression. Altogether,
these results support the ability of MSCs to differentiate into neuron-like cells
in response to CoCl(2), an effect that might act, in part, through HIF-1
activation and cell-cycle arrest, and which is potentiated by inhibition of ROCK.
PMID: 16772336 [Indexed for MEDLINE]