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

• Authors: Lauren A Hymel, Georgia Institute of Technology; Shannon E Anderson, Georgia Institute of Technology; Thomas C Turner, Georgia Institute of Technology; William Y York, Georgia Institute of Technology; Hongmanlin Zhang, Georgia Institute of Technology; Adrian R Liversage, University of Georgia; Hong Seo Lim, Georgia Institute of Technology; Peng Qiu, Georgia Institute of Technology; Luke J Mortensen, University of Georgia; Young C Jang, Emory University; Nick J Willett, Emory University; Edward A Botchwey, Georgia Institute of Technology
• Journal Title: COMMUNICATIONS BIOLOGY
• Volume: Volume 6, Number 1
• Publisher: NATURE PORTFOLIO | 2023-07-19, Pages 749-749
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s42003-023-04790-6
• Subjects: Biology, General; Engineering, Biomedical; Engineering, Materials Science; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biology; Multidisciplinary Sciences; Life Sciences & Biomedicine - Other Topics; Science & Technology - Other Topics; REGULATORY T-CELLS; SKELETAL-MUSCLE; MACROPHAGE PHENOTYPE; REGENERATION; ACTIVATION; HIERARCHY; INJURY; MOUSE; VISUALIZATION; ACCUMULATION

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.