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  current news   Press   selected story    
     
  4th August  
 

Heparan sulfate increases the self-renewal of hMSCs through convergence of multiple pathways.

 
 




Authors
Christian Dombrowski, Torben Helledie, Victor Nurcombe, Simon M. Cool.

Congratulations to Dr. Christian Dombrowski who was awarded the John Haddad Young Investigator Award at the Advances in Mineral Metabolism (AIMM)-ASBMR John Haddad Young Investigators Meeting held April 8-12, 2008, in Snowmass, Colorado, USA.  Dr. Dombrowski received this prize for his research on the potential of heparan sulfate to increase the self-renewal of human Mesenchymal Stem Cells (hMSCs), conducted under the mentorship of Associate Professor Victor Nurcombe and Dr. Simon Cool at the IMCB. This work is helping to unravel the mechanism of action of heparan sulfate and its role in potentiating the activation of signalling pathways in cells.

Abstract
We recently identified a species of heparan sulfate (HS) that increases the self-renewal of na´ve human mesenchymal stem cells (hMSCs). Understanding the mechanism of self-renewal of these cells is critical for their development as a therapeutic tool and we exploited the opportunity provided by HS to investigate this further. Preliminary results suggested that HS prevents the up-regulation of inhibitors of the TGFβ pathway, yet growth factors from the TGF-β family are not known to be mitogenic to hMSC. Indeed, supplementing hMSC cultures with Activin, Nodal or TGF-β3 alone failed to stimulate proliferation but, surprisingly, they synergized with the HS carbohydrate to yield a four-fold increase in cell number as compared to control cells, suggesting that normal TGF-β signalling was profoundly modified. Gene profiling revealed that the combination of HS and TGF-β3 resulted in the upregulation of Wnt pathway targets, and TOPFLASH reporter assays confirmed that it significantly increased WNT signalling. Our results uncovered a novel mechanism whereby HS can drive the proliferation of hMSC by diverting TGF-β signaling towards the Wnt pathway.

 
 



 
 

Figure & Legend: HS induces proliferation of hMSC by diverting TGF-▀ signaling towards the WNT pathway. (A) hMSCs were cultured for 6 days with growth factors from the TGF-▀ family, alone or in combination with heparan sulfate before total viable cell number was measured. (B) Micrograph of hMSCs cultured in different conditions. (C) Cells were cultured for 6 days in control or HS supplemented media and transfected with a Wnt reporter (TOPFLASH).and seeded in media alone or supplemented with TGF-▀3 for 48 hours before luciferase measurement.