Scaling up stem cell production can make regenerative therapy for osteochondral defects a reality.

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Scaling up stem cell production

18 May 2020

By enhancing stem cell proliferation, this newly developed bio-additive lowers the barriers to regenerative medicine.

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.

An international collaboration by scientists at A*STAR’s Institute of Medical Biology (IMB), the National University of Singapore and the Mayo Clinic in the United States has 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 Simon Cool, a 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 sulfate glycosaminoglycan bio-additive to stabilize and prolong the proliferative effects of FGF2.

“Our inventive step was to utilize affinity chromatography, a very efficient and cost-effective technique, to manufacture a particular heparan sulfate variant with increased binding potential for FGF2,” said Cool.

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).

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Ling, L., Ren, X., Cao, X., Hassan, A.B.M., Mah, S., et al. Enhancing the efficacy of stem cell therapy with glycosaminoglycans. Stem Cell Reports 14: 105-121 (2020) | article

About the Researcher

Simon Cool

Research Director

Institute of Molecular and Cell Biology
Simon Cool received his BSc (hons) and PhD degrees from the University of Queensland in Brisbane, Australia, where he subsequently held a faculty position in the School of Biomedical Sciences. He joined A*STAR’s Institute of Molecular and Cell Biology (IMCB) in 2003 as a Principal Investigator, followed by A*STAR’s Institute of Medical Biology (IMB) in 2008, shortly after its inception. In October 2020, Cool returned to IMCB as a Research Director. He leads the Glycotherapeutics Group, where he is focused on developing novel glycosaminoglycan biomolecules that enhance wound repair and control adult human mesenchymal stem cell activity. Cool is an Adjunct Professor (Research) in the Orthopaedic Department at the National University of Singapore. He has filed over 50 patent applications and he serves as Section Editor for the Journal of Molecular Histology, and on the editorial boards of Biomaterials, and Stem Cells and Development. Cool is also Treasurer of the Tissue Engineering and Regenerative Medicine International Society (TERMIS), Asia Pacific Chapter and Vice-Treasurer of the Stem Cell Society Singapore (SCSS).

This article was made for A*STAR Research by Wildtype Media Group