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GSTT1 – The Key to The Widespread Therapeutic Application of Human Mesenchymal Stem Cells?

Review of “A genomic biomarker that identifies human bone marrow‐derived mesenchymal stem cells with high scalability” from STEM CELLS by Stuart P. Atkinson

A previous STEM CELLS study from researchers led by Lawrence W. Stanton (Hamad Bin Khalifa University, Doha, Qatar) and Simon M. Cool (Agency for Science, Technology and Research, Singapore) previously established criteria that allowed for the identification of human bone marrow-derived mesenchymal stem cells (MSCs) with increased proliferative potential, enhanced clonogenicity, possessed longer telomeres, overexpressed levels of specific cell surface markers, and most importantly, displayed improved ectopic bone-forming ability [1]. Next, the authors hoped to circumvent problems related to donor-to-donor heterogeneity and the loss of cell function during long-term ex vivo culture expansion by developing a biomarker strategy that would readily identify MSCs with increased inherent therapeutic potential. 

Towards this goal, the authors now return with a new STEM CELLS article [2] in which they describe the identification of glutathione S‐transferase theta 1 (GSTT1), which belongs to a family of enzymes that catalyze the conjugation of glutathione to a range of electrophilic compounds to prompt their detoxification, as a novel genomic DNA biomarker for human MSC scalability.

The authors of this fascinating new study employed microarray analysis to pinpoint the transcriptomic differences that provided “high-growth capacity” MSCs with their enhanced capabilities. Interestingly, this analysis found that “lower-growth capacity” MSCs overexpressed GSTT1 by 50-fold, while high-growth capacity MSCs suffered from low GSTT1 expression due to a gene deletion. 

Furthermore, Sathiyanathan et al. confirmed that GSTT1-null MSCs grew more rapidly and displayed enhanced clonogenicity and longer telomeres when compared to GSTT1‐positive MSCs, which possessed lower growth capacity; furthermore, suppressing GSTT1 in MSCs prompted an increase in cell growth without adversely affecting their multilineage differentiation potential, thereby highlighting GSTT1 as a biomarker for MSC quality and scalability

Given these data, the authors propose the development of GSTT1 as a DNA biomarker used to prospectively screen donors before the bone marrow isolation for MSC collection. The choice of those MSCs amenable to extended ex vivo expansion without losing their stemness or function may allow for reductions in manufacturing time and cost, thereby fostering the creation of more affordable MSC‐based therapies. The authors also anticipate the combination of GSTT1 as a biomarker with additional MSC culture improvements, such as the implementation of microcarriers [3, 4] and media formulations [5, 6] to further boost the therapeutic applicability of hMSCs to human disease.

For more on GSTT1 and the promise of improved MSC-based therapeutics, stay tuned to the Stem Cells Portal!


References

  1. Samsonraj RM, Rai B, Sathiyanathan P, et al., Establishing Criteria for Human Mesenchymal Stem Cell Potency. STEM CELLS 2015;33:1878-1891.
  2. Sathiyanathan P, Samsonraj RM, Tan CLL, et al., A genomic biomarker that identifies human bone marrow-derived mesenchymal stem cells with high scalability. STEM CELLS 2020;38:1124-1136.
  3. Lam AT-L, Li J, Toh JP-W, et al., Biodegradable poly-caprolactone microcarriers for efficient production of human mesenchymal stromal cells and secreted cytokines in batch and fed-batch bioreactors. Cytotherapy 2017;19:419-432.
  4. Tavassoli H, Alhosseini SN, Tay A, et al., Large-scale production of stem cells utilizing microcarriers: A biomaterials engineering perspective from academic research to commercialized products. Biomaterials 2018;181:333-346.
  5. Chen AK-L, Chew YK, Tan HY, et al., Increasing efficiency of human mesenchymal stromal cell culture by optimization of microcarrier concentration and design of medium feed. Cytotherapy 2015;17:163-173.
  6. Tan KY, Reuveny S, and Oh SKW, Recent advances in serum-free microcarrier expansion of mesenchymal stromal cells: Parameters to be optimized. Biochemical and Biophysical Research Communications 2016;473:769-773.