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Improving Mesenchymal Stem Cell Therapies with TSG‐6

Review of “TNF‐Stimulated Gene‐6 Is a Key Regulator in Switching Stemness and Biological Properties of Mesenchymal Stem Cells” from STEM CELLS by Stuart P. Atkinson

The general lack of clinical effectiveness of mesenchymal stem cell (MSC) therapy may derive from cellular heterogeneity in the transplanted cells [1]; however, we lack specific biomarkers that can predict the therapeutic potential of MSCs and, therefore, aid in the generation of a more homogenous and effective cell product that provides for enhanced patient outcomes. 

As a step towards this goal, researchers led by Stefania Vetrano (Humanitas University, Milan, Italy) investigated the expression and activity of tumor necrosis factor‐stimulated protein 6 (also known as TNF‐stimulated gene‐6 or TSG‐6), an anti‐inflammatory factor [2] with the capacity to regulate matrix organization/function [3]. Interestingly, studies have demonstrated that MSCs secrete TSG-6 and that TSG‐6 plays a crucial role in the therapeutic output of MSCs [3-5]. 

Reporting in STEM CELLS, Romano et al. now apply engineered murine MSCs as an investigative tool to demonstrate how TSG-6 regulates stemness and directs various cellular functions in a study that may prompt improve therapeutic outcomes in human MSC-based clinical applications [6].

The authors began by comparing gene expression profiles of wild type and TSG-6 knockout MSCs, discovering that a loss of autocrine TSG-6 activity prompted alterations to the expression of genes in pathways crucial to the normal function of MSCs. Furthermore, the study detected morphological changes marked by cytoskeletal alterations, a reduction in the size of extracellular vesicles, a decrease in MSC proliferation rate, and the inhibition of adipogenic, osteogenic, and chondrogenic differentiation ability following TSG-6 knockout in MSCs. 

Of considerable interest, TSG-6 knockout MSCs also released higher levels of Interleukin 6 when compared to wild type MSCs, suggesting that a loss of TSG-6 paracrine function inhibits the immunomodulatory capacity of MSCs while enhancing pro‐tumorigenic properties [7]. However, the supplementation of knockout cells with extracellular matrix components and exogenous TSG-6 rescued many of the alterations observed as a consequence of TSG-6 knockout, suggesting the general importance of the extracellular matrix environment to TSG-6 function.

These data suggest that isolating cells as a function of TSG-6 expression may provide a means to generate a homogenous and therapeutically relevant cell product. Furthermore, monitoring TSG-6 levels in vivo may also represent a useful marker of antitumorigenic risk and a predictive tool for monitoring the effectiveness of immunomodulatory and regenerative therapies. To this end, the authors now hope to study TSG-6 in human MSCs and explore the link between Interleukin 6 and TSG‐6 further.

For more on how markers such as TSG-6 will foster the development of enhanced MSC-based therapies, stay tuned to the Stem Cells Portal!


  1. Phinney DG, Functional heterogeneity of mesenchymal stem cells: Implications for cell therapy. Journal of Cellular Biochemistry 2012;113:2806-2812.
  2. Milner CM and Day AJ, TSG-6: a multifunctional protein associated with inflammation. Journal of Cell Science 2003;116:1863.
  3. Day AJ and Milner CM, TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties. Matrix Biology 2019;78-79:60-83.
  4. Lee RH, Pulin AA, Seo MJ, et al., Intravenous hMSCs Improve Myocardial Infarction in Mice because Cells Embolized in Lung Are Activated to Secrete the Anti-inflammatory Protein TSG-6. Cell Stem Cell 2009;5:54-63.
  5. Lee RH, Yu JM, Foskett AM, et al., TSG-6 as a biomarker to predict efficacy of human mesenchymal stem/progenitor cells (hMSCs) in modulating sterile inflammation in vivo. Proceedings of the National Academy of Sciences 2014;111:16766.
  6. Romano B, Elangovan S, Erreni M, et al., TNF-Stimulated Gene-6 Is a Key Regulator in Switching Stemness and Biological Properties of Mesenchymal Stem Cells. STEM CELLS 2019;37:973-987.
  7. Fisher DT, Appenheimer MM, and Evans SS, The two faces of IL-6 in the tumor microenvironment. Seminars in Immunology 2014;26:38-47.