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Expression profiling and functional analysis of Wnt signalling mechanisms in mesenchymal stem cells

Etheridge, S.L., Spencer, G.J., Heath, D.J. and Genever, P.G. (2008) Expression profiling and functional analysis of Wnt signalling mechanisms in mesenchymal stem cells. Stem Cells, 22 (5). pp. 849-860. ISSN 1066-5099

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Abstract

Through their broad differentiation potential, mesenchymal stem cells (MSCs) are candidates for a range of therapeutic applications, but the precise signaling pathways that determine their differentiated fate are not fully understood. Evidence is emerging that developmental signaling cues may be important in regulating stem cell self-renewal and differentiation programs. Here we have identified a consistent expression profile of Wnt signaling molecules in MSCs and provide evidence that an endogenous canonical Wnt pathway functions in these cells. Wnts bind to Frizzled (Fz) receptors and subsequent canonical signaling inhibits glycogen synthase kinase-3 (GSK-3), causing -catenin translocation into the nucleus to induce target gene expression. In human MSCs isolated from bone marrow of different donors, we appear to have identified a common Wnt/Fz expression profile using reverse transcriptase polymerase chain reaction (RT-PCR). Associated Wnt signaling components, including low-density lipoprotein receptor-related protein-5 (LRP-5), kremen-1, dickkopf-1 (Dkk-1), secreted Frizzled-related peptide (sFRP)-2, sFRP3, sFRP4, Disheveled (Dvl), GSK-3, adenomatous polyposis coli (APC), -catenin, T-cell factor (TCF)-1, and TCF-4, were also identified. Nuclear -catenin was observed in 30%-40% of MSCs, indicative of endogenous Wnt signaling. Exposure to both Wnt3a and Li+ ions, which promotes canonical Wnt signaling by inhibiting GSK-3, reduced phosphorylation of -catenin in MSCs and increased -catenin nuclear translocation approximately threefold over that of the controls. Our findings indicate that autocrine Wnt signaling operates in primitive MSC populations and supports previous evidence that Wnt signaling regulates mesenchymal lineage specification. The identification of a putative common Wnt/Fz molecular signature in MSCs will contribute to our understanding of the molecular mechanisms that regulate self-renewal and lineage-specific differentiation.

Item Type: Article
Institution: The University of York
Academic Units: The University of York > Biology (York)
Depositing User: York RAE Import
Date Deposited: 16 Feb 2009 14:51
Last Modified: 16 Feb 2009 14:51
Published Version: http://dx.doi.org/10.1634/stemcells.22-5-849
Status: Published
Publisher: AlphaMed Press
Identification Number: 10.1634/stemcells.22-5-849
URI: http://eprints.whiterose.ac.uk/id/eprint/7511

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