Neutrophil and natural killer cell imbalances prevent muscle stem cell–mediated regeneration following murine volumetric muscle loss

Abstract

Significance Skeletal muscle is one of the largest tissues in the body and can regenerate when damaged through a population of resident muscle stem cells. A type of muscle trauma called volumetric muscle loss overwhelms the regenerative capacity of muscle stem cells and engenders fibrotic supplantation. A comparison of muscle injuries resulting in regeneration or fibrosis revealed that intercellular communication between neutrophils and natural killer cells impacts muscle stem cell-mediated repair. Perturbation of neutrophil–natural killer cell interactions resulted in a variation of healing outcomes and suggested that immunomodulatory interventions can be effective to prevent aberrant healing outcomes.

Intravital microscopy of satellite cell dynamics and their interaction with myeloid cells during skeletal muscle regeneration

“…5a, d-f). These RFP - NADH + cells probably included neutrophils, resident macrophages, and fibro/adipogenic progenitors (FAPs), which could regulate MuSCs functionally, but the density of FAPs increased much more slowly than infiltrating neutrophils which peaked around 24 hpi 7,8,10,28,35,76,77 . Therefore, we reasoned that most RFP - NADH + cells observed were neutrophils; next, we performed immunostaining in the whole-mount TA muscle using fluorophore-conjugated antibodies of neutrophils (Gr-1 and Ly6G) and found that more than 85% of NADH + cells were Gr-1 + or Ly6G + in Injured-GC and Injured-GC mice at 1.5 dpi (Supplementary Figs.…”

“…5a, d-f). These RFP -NADH + cells probably included neutrophils, resident macrophages, and fibro/adipogenic progenitors (FAPs), which could regulate MuSCs functionally, but the density of FAPs increased much more slowly than infiltrating neutrophils which peaked around 24 hpi 7,8,10,28,35,76,77 .…”

“…Numerous studies have shown that macrophages or neutrophils regulate the dynamics of MuSCs via paracrine factor release 28,30,31,32,33,34,35 . However, only a few studies have reported that cell-cell contacts play an essential role in regulating the fate of MuSCs.…”

Human muscle in gene edited pigs for treatment of volumetric muscle loss

“…While much of the current clinical understanding arises from functional data and observations from those injured ( Mase et al, 2010 ; Garg et al, 2015 ; Dziki et al, 2016 ); our knowledge of the pathophysiology and mechanisms of failed regeneration has emerged from rodent and porcine models ( Corona et al, 2016 ; Greising et al, 2019 ) which is paramount to the development of new technologies for transplant sources. Two aspects of the pathophysiology of the muscle at the initially VML injury site are vital to understanding, developing and evaluating treatments; 1) the lost muscle at the primary injury site (i.e., the local muscle environment after injury), failed regeneration, pathological fibrosis ( Corona et al, 2020 ), chronic and heightened inflammation ( Larouche et al, 2022 ), and altered force transmission and muscle architecture ( Goldman et al, 2021 ); and 2) progressive secondary injury to non-injured muscle and systemic insults such as motor neuron axotomy ( Corona et al, 2018 ), denervation ( Sorensen et al, 2021 ), and metabolic inflexibility ( Dalske et al, 2021 ). Multiple potential therapeutic targets exist because the functional deficit is not solely due to the loss of muscle tissue, however, skeletal muscle transplantation near the time of injury could both improve function and prevent the progressive, secondary injury.…”

Histological Methods to Assess Skeletal Muscle Degeneration and Regeneration in Duchenne Muscular Dystrophy

“…Although Ly-6G, an anchored surface protein implicated in tissue neutrophil extravasation, is the most widely used marker to recognise mouse neutrophils by immunohistology [82], both mouse and human neutrophils have also been identified in the literature with antibodies against Ly-6B2 or enzymes contained in their granules, such as MPO (Table 2), albeit never in dystrophic muscles.…”