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Macrophages: The Missing Ingredient of Functional 3D Tissue-engineered Muscle Constructs?

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Review of “Incorporation of macrophages into engineered skeletal muscle enables enhanced muscle regeneration” from Nature Biomedical Engineering by Stuart P. Atkinson 

Muscle satellite cells (MuSCs) activate in response to damage and asymmetrically divide to both self-renew and generate proliferative myogenic precursor cells that promote skeletal muscle regeneration [1]. However, in cases such as severe muscle loss or chronic degenerative diseases, insufficiencies in the natural regeneration process have prompted the development of three-dimensional (3D) tissue-engineered muscle constructs as an alternative treatment strategy.

Researchers from the laboratory of Nenad Bursac (Duke University, Durham, NC, USA) aimed to develop advanced 3D tissue-engineered muscle constructs by not only considering the physical interactions between the MuSCs, myofibers, and extracellular matrix (ECM), but by also seeking to understand the potentially vital role of immune cells [2, 3]. Now, in a Nature Biomedical Engineering article, Juhas et al. report that macrophages limit myofiber apoptosis and attenuate the pro-inflammatory environment induced by muscle damage, enable self-repair of muscle, and enhance blood vessel ingrowth, cell survival, and contractile function in vivo [4]. Are macrophages the missing ingredient of 3D tissue-engineered muscle constructs?

Initial in vitro analysis of an adult rat-derived 3D tissue-engineered muscle constructs failed to uncover significant muscle repair following the cell damage associated with cardiotoxic injury even in the presence of established pro-regenerative cytokines. However, the addition of rat or human macrophages permitted a natural regenerative response, allowing almost total structural and functional repair by supporting MuSC proliferation and differentiation, limiting myofiber apoptosis and degeneration, and attenuating the disease-associated pro-inflammatory environment. 

Finally, in vivo analyses employed a mouse dorsal window-chamber model, which allowed repeated intravital assessments of implanted engineered muscle tissue. Encouragingly, the addition of macrophages enhanced blood vessel ingrowth, cell survival, muscle regeneration, and contractile function, although at a slower pace when compared to the in vitro model.

The authors hope that their identification of macrophages as the missing part of 3D tissue-engineered muscle constructs will aid the development of a model system of muscle repair to aid the identification of novel pro-regenerative factors. Furthermore, they anticipate that the demonstrated importance of immune cells will inspire a broader application in transplanted tissue grafts and that ongoing studies into human and even patient-specific muscle constructs will soon bear fruit.

For more on muscle regeneration and the importance of the immune system, stay tuned to the Stem Cells Portal!

References

  1. Charge SB and Rudnicki MA, Cellular and molecular regulation of muscle regeneration. Physiological Reviews 2004;84:209-38.
  2. Tidball JG, Regulation of muscle growth and regeneration by the immune system. Nature Reviews Immunology 2017;17:165-178.
  3. Saclier M, Yacoub-Youssef H, Mackey AL, et al., Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration. STEM CELLS 2013;31:384-96.
  4. Juhas M, Abutaleb N, Wang JT, et al., Incorporation of macrophages into engineered skeletal muscle enables enhanced muscle regeneration. Nature Biomedical Engineering 2018;2:942-954.