Identifying dysregulated immune cell subsets following volumetric muscle loss with pseudo-time trajectories

• Published in: Communications biology 2023-07, Vol.6 (1), p.749-749, Article 749
• Main Authors: Hymel, Lauren A., Anderson, Shannon E., Turner, Thomas C., York, William Y., Zhang, Hongmanlin, Liversage, Adrian R., Lim, Hong Seo, Qiu, Peng, Mortensen, Luke J., Jang, Young C., Willett, Nick J., Botchwey, Edward A.
• Format: Article
• Language: English
• Subjects: 13/1; 13/21; 13/31; 14/19; 631/250/256/2515; 64/60; 692/699/578; 82/51; Animal models; Animals; Biology; Biomedical and Life Sciences; Collagen; Immune system; Inflammation; Injuries; Life Sciences; Localization; Lymphocytes T; Macrophages; Mice; Microenvironments; Muscle, Skeletal - pathology; Muscular Diseases - pathology; Muscular Diseases - therapy; Phenotypes; Quadriceps muscle; Regeneration; Regenerative Medicine
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-04790-6

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 CD206 hi Ly6C hi ‘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. The immune cell dynamics that influence the pathological phenotype of a critical volumetric muscle loss (VML) injury that cannot regenerate versus a subcritical injury capable of regeneration are characterized using quadriceps VML mouse models.