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Extensive damage to skeletal muscle tissue due to volumetric muscle loss (VML) is beyond the inherent regenerative capacity of the body, and results in permanent functional debilitation. Current clinical treatments fail to fully restore native muscle function. Recently, cell-based therapies have emerged as a promising approach to promote skeletal muscle regeneration following injury and/or disease. Stem cell populations, such as muscle stem cells, mesenchymal stem cells and induced pluripotent stem cells (iPSCs), have shown a promising capacity for muscle differentiation. Support cells, such as endothelial cells, nerve cells or immune cells, play a pivotal role in providing paracrine signaling cues for myogenesis, along with modulating the processes of inflammation, angiogenesis and innervation. The efficacy of cell therapies relies on the provision of instructive microenvironmental cues and appropriate intercellular interactions. This review describes the recent developments of cell-based therapies for the treatment of VML, with a focus on preclinical testing and future trends in the field.
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Identifying dysregulated immune cell subsets following volumetric muscle loss with pseudo-time trajectories
Abstract Volumetric muscle loss (VML) results in permanent functional deficits and remains a substantial regenerative medicine challenge. A coordinated immune response is crucial for timely myofiber regeneration, however the immune response following VML has yet to be fully characterized. Here, we leveraged dimensionality reduction and pseudo-time analysis techniques to elucidate the cellular players underlying a functional or pathological outcome as a result of subcritical injury or critical VML in the murine quadriceps, respectively. We found that critical VML resulted in a sustained presence of M2-like and CD206hiLy6Chi‘hybrid’ macrophages whereas subcritical defects resolved these populations. Notably, the retained M2-like macrophages from critical VML injuries presented with aberrant cytokine production which may contribute to fibrogenesis, as indicated by their co-localization with fibroadipogenic progenitors (FAPs) in areas of collagen deposition within the defect. Furthermore, several T cell subpopulations were significantly elevated in critical VML compared to subcritical injuries. These results demonstrate a dysregulated immune response in critical VML that is unable to fully resolve the chronic inflammatory state and transition to a pro-regenerative microenvironment within the first week after injury. These data provide important insights into potential therapeutic strategies which could reduce the immune cell burden and pro-fibrotic signaling characteristic of VML.
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- Award ID(s):
- 1648035
- PAR ID:
- 10522578
- Publisher / Repository:
- Nature
- Date Published:
- Journal Name:
- Communications Biology
- Volume:
- 6
- Issue:
- 1
- ISSN:
- 2399-3642
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s42003-023-04790-6
