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Research Interest:
If we are to realize the therapeutic potential of stem cells, controlling lineage-specific decisions is paramount. The Stem Cell and Tissue Repair Group is focused on determining how elements of the extracellular matrix within the stem cell niche, and most particularly the glycosaminoglycan (GAG) sugars, protect, hold and present crucial growth factors to embryonic and adult stem cells, thus controlling intracellular signaling cascades and ultimately cell fate decisions. This crucial and fundamental process, central to all tissue growth and repair, is little understood because of the complexity of GAG sugar structures and their tissue- and temporally-specific expression patterns.
There is growing evidence that such sugars are not randomly synthesized, but contain specific domains that couple active molecules together. Amongst the most interesting of the sugars are the heparan sulfates, a family that is now known to be bewilderingly complex. The most famous of the heparan sulfates is the variant called heparin, the anticoagulant agent, which is perhaps the most successful drug ever developed by Medical Science. In 1993 our group pioneered the analysis of the first detailed mapping of developmentally-relevant heparan sugar motifs from embryonic tissue, and showed how they cued the expression of fibroblast growth factors (FGFs) during stem cell growth (Nurcombe et al., Science 1993). We are thus the first group in the world to have purified and characterized an embryonic heparan GAG of known specific action.
Since this early analysis we and others have shown that over 80 growth and adhesive molecules are dependent on heparan sulfate binding for their bioactivity, most notably sonic hedgehog, the BMPs, the FGFs, the VEGFs, the PDGFs, GM-CSF as well as the collagens, laminins and fibronectin (Nurcombe et al., J. Biol. Chem. 1995, 1998, 2000, 2002). Moreover, as each stem cell grows and then differentiates, it puts on its surface a different complement of heparan sugars to capture the different mixtures of bioactive peptides it needs to drive its developmental program. Subsequently our group has subjected a range of tissue-specific heparan sulfates to intense structural analysis; to do so, we have assembled a stem cell HS library, derived from embryonic, placental and adult stem cells.
Based on high throughput screening, several of these heparan GAG species offer what we believe are unique therapeutic advantages for tissue repair. To this end, how bone marrow stromal stem cells respond when challenged by various HS/HS-growth factor combinations both in vitro and in various wound-healing models has become a major focus of our translational program (Cool et al., Int. J. Dev. Biol, 2002; Cool et al., BBRC, 2005; Cool et al., Stem Cells & Dev., 2006). Most recently, an in vivo bone fracture model successfully treated by HS therapy (Jackson, Nurcombe, Cool, J. Orthopaedic Res. 2006) has resulted in much commercial interest. Following on from these exciting results, A*STAR’s Exploit Technologies is developing a Patent and Trade Secrets strategy to help protect and develop our growing portfolio.
Furthermore, with the help of commercial partners, most notably New Zealand’s Industrial Research Ltd., we are seeking to further strengthen our ability to biochemically synthesize these novel molecules, a first step in exploiting this technology. Most recently, we have began animal trials with Smith and Nephew, UK using a combination of HS and implantable hydroxyapatite to improve the healing of critical-sized bone defects.
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