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Muscle Stem Cells – New Players in the Treatment of Inflammatory Diseases?

Review of "Skeletal Muscle Stem Cells Confer Maturing Macrophages Anti-inflammatory Properties through IGF-2" from STEM CELLS Translational Medicine by Stuart P. Atkinson

Interactions between immune cells and muscle stem cells (MuSCs) within skeletal muscle influence the success of tissue repair and regeneration; however, we still lack a clear understanding of how MuSCs regulate the function of cells such as monocytes and macrophages. Given recent studies establishing that tissue stem cells can reprogram macrophage fate via metabolic rewiring [1, 2], researchers led by Changshun Shao and Yufang Shi (Medical College of Soochow University, Suzhou, Jiangsu, China) hypothesized that MuSCs may also impact the metabolism and function of macrophages, and may, therefore, represent a novel treatment approach for certain inflammatory disorders. Now, in a new STEM CELLS Translational Medicine article, the team describes their investigations into immunomodulation following the transplantation of MuSCs into a mouse model of inflammatory bowel disease [3].

Fang et al. found that a single intravenous administration of in vitro cultured MuSCs or MuSC-conditioned medium to a chemically-induced mouse model of inflammatory bowel disease prompted a robust anti‐inflammatory effect and improvements to many symptoms; however, the depletion of macrophages by the treatment of mice with clodronate liposomes negated the formation of an anti-inflammatory environment suitable for repair/regeneration. 

Moving in vitro to gain mechanistic insight, the authors discovered that MuSC-conditioned medium reduced the expression of inflammatory cytokines and increased the expression of programmed death‐ligand 1 (PDL-1), an anti‐inflammatory molecule known to attenuate immune responses and maintain immune homeostasis [4, 5], in macrophages activated by exposure to pro-inflammatory signals. Additionally, MuSCs produced and secreted elevated levels of insulin‐like growth factor‐2 (IGF‐2), which promoted the polarization of macrophages from a pro-inflammatory phenotype into an anti-inflammatory phenotype by inducing a metabolic switch from glycolysis towards oxidative phosphorylation [6]. 

The authors next highlighted the overall importance of MuSC-secreted IGF-2 by establishing the loss of any anti‐inflammatory effects following the knockdown or neutralization of IGF‐2 in vitro and in vivo, where the loss of IGF-2 production and secretion negated the therapeutic effects of MuSCs administered to inflammatory bowel disease model mice. Finally, and perhaps most importantly, the study also highlighted the fact that MuSCs express much higher levels of IGF‐2 when compared to bone marrow-derived mesenchymal stem cells, the typical go-to cell type for the treatment of inflammatory disorders, thereby suggesting a shift of focus for stem cell therapeutic approaches to inflammatory diseases.

The authors have established that MuSCs can create an anti-inflammatory environment that supports tissue repair/regeneration by IGF-2 secretion via the modulation of macrophage metabolism and their subsequent polarization into an anti-inflammatory phenotype. Can we now exploit this mechanism to improve the treatment of conditions such as inflammatory bowel disease in human patients?

For the answers to this question, and more on the therapeutic relevance of muscle stem cells beyond muscle repair and regeneration, stay tuned to the Stem Cells Portal!

References

  1. Du L, Lin L, Li Q, et al., IGF-2 Preprograms Maturing Macrophages to Acquire Oxidative Phosphorylation-Dependent Anti-inflammatory Properties. Cell Metabolism 2019;29:1363-1375.e8.
  2. Peruzzotti-Jametti L, Bernstock JD, Vicario N, et al., Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation. Cell Stem Cell 2018;22:355-368.e13.
  3. Fang J, Zhang S, Liu Z, et al., Skeletal muscle stem cells confer maturing macrophages anti-inflammatory properties through insulin-like growth factor-2. STEM CELLS Translational Medicine 2020;9:773-785.
  4. Trabattoni D, Saresella M, Pacei M, et al., Costimulatory Pathways in Multiple Sclerosis: Distinctive Expression of PD-1 and PD-L1 in Patients with Different Patterns of Disease. The Journal of Immunology 2009;183:4984.
  5. Sun C, Mezzadra R, and Schumacher TN, Regulation and Function of the PD-L1 Checkpoint. Immunity 2018;48:434-452.
  6. Kelly B and O'Neill LAJ, Metabolic Reprogramming in Macrophages and Dendritic Cells in Innate Immunity. Cell Research 2015;25:771-784.