High impact sports such as soccer and basketball place athletes at risk for injuries called osteochondral defects. These defects occur when the soft tissue between joints—known as cartilage—become damaged, causing pain and a limited range of motion that could threaten an athlete’s career.
Current approaches in repairing osteochondral defects, including microfracturing and grafting, provide only limited success. Next-generation stem cell therapy using human mesenchymal stem cells (hMSCs) could help restore worn out cartilage. However, obtaining enough stem cells to achieve therapeutic efficacy has long been a major obstacle to this approach.
In a joint study by scientists at A*STAR’s Institute of Medical Biology (IMB), the National University of Singapore and the Mayo Clinic have now made significant strides towards making stem cell therapy feasible by developing an ingenious method for enhancing in vitro hMSC proliferation. Their findings have been patented in the US.
Human MSCs require certain growth factors to support their proliferation, one of which is fibroblast growth factor 2 (FGF2). However, FGF2 is expensive and its ability to induce proliferation is short-lived. At the same time, “previous work has shown that prolonged FGF2 supplementation can adversely affect the therapeutic potential of hMSCs,” said Dr. Simon Cool, Senior Principal Investigator at IMB and the study’s senior author.
Harnessing the knowledge that hMSCs themselves produce low levels of FGF2, Cool and colleagues developed a heparan sulphate (HS) glycosaminoglycan bio-additive to stabilize and prolong the proliferative effects of FGF2.
“HS glycosaminoglycans are key extracellular matrix components known to regulate the activity of growth factors needed for stem cell self-renewal and lineage fate decisions,” Cool explained. “Our inventive step was to utilize affinity chromatography, a very efficient and cost-effective technique, to manufacture a particular HS variant with increased binding potential for FGF2.”
This variant, named HS8, enabled hMSC cultures to produce about 2.6 times more cells than cultures without HS8. By studying animal models of osteochondral defects, the team demonstrated that HS8-expanded hMSCs produced significant improvements, based on a widely-used clinical grading system.
Besides repairing sports-related injuries, HS8-expanded hMSCs could also be used to supply hospitals with large numbers of highly potent stem cells to treat a rapidly aging population in need of cellular therapy, Cool added.
“We are currently investigating changes in cell and tissue aging pathways and whether HS8 affects these processes. Also, HS glycosaminoglycans are required for the binding of FGF2 to FGF receptor 1 (FGFR1) and the establishment of intracellular FGF signals. Mechanistic studies are underway to determine whether FGF2-HS8 complexes bind and then maximally activate FGFR1, and whether this relationship is altered in the context of cellular aging,” he concluded.
The A*STAR-affiliated researcher contributing to this research is from the Institute of Medical Biology (IMB).