Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration

Abstract

SUMMARYMuscle regeneration requires the coordinated interaction of multiple cell types. Satellite cells have been implicated as the primary stem cell responsible for regenerating muscle, yet the necessity of these cells for regeneration has not been tested. Connective tissue fibroblasts also are likely to play a role in regeneration, as connective tissue fibrosis is a hallmark of regenerating muscle. However, the lack of molecular markers for these fibroblasts has precluded an investigation of their role. Using Tcf4, a newly identified fibroblast marker, and Pax7, a satellite cell marker, we found that after injury satellite cells and fibroblasts rapidly proliferate in close proximity to one another. To test the role of satellite cells and fibroblasts in muscle regeneration in vivo, we created Pax7CreERT2 and Tcf4 CreERT2 mice and crossed these to R26R DTA mice to genetically ablate satellite cells and fibroblasts. Ablation of satellite cells resulted in a complete loss of regenerated muscle, as well as misregulation of fibroblasts and a dramatic increase in connective tissue. Ablation of fibroblasts altered the dynamics of satellite cells, leading to premature satellite cell differentiation, depletion of the early pool of satellite cells, and smaller regenerated myofibers. Thus, we provide direct, genetic evidence that satellite cells are required for muscle regeneration and also identify resident fibroblasts as a novel and vital component of the niche regulating satellite cell expansion during regeneration. Furthermore, we demonstrate that reciprocal interactions between fibroblasts and satellite cells contribute significantly to efficient, effective muscle regeneration.

Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells

“…Very recently, three reports [46][47][48] showed that selective ablation of Pax7-expressing satellite cells during adult life permanently hampers subsequent attempts to regenerate skeletal muscles, leading to the conclusion that no other endogenous cell types may substitute for satellite cells. These results are not in contradiction with those reported here for the following reasons: the ablation of Pax7 + satellite cells was carried out in adult mice, at an age when the contribution of AP + pericyets to muscle regeneration becomes negligible.…”

p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

“…Satellite cells are the principal muscle stem cell [1][2][3][4], responsible for the majority of postnatal growth and repair [5], and are capable of remarkable regenerative capability [6]. In response to extracellular stimuli, they activate and undergo a crucial proliferative expansion, before either returning to quiescence or differentiating and fusing to existing myofibers.…”

Cell Transplantation and “Stem Cell Therapy” in the Treatment of Myopathies: Many Promises in Mice, Few Realities in Humans

“…It remains to determine to what extent these other myogenic cells play a physiological role in myofiber regeneration, and if so, how they play this role. The most consistent evidence at present indicates that the main role in myofiber regeneration is played by satellite cells and myoblasts [43][44][45][46]. The question that is still pending is to what extent the role of satellite cells in myofiber regeneration is the principal over other accessory regeneration pathways, or whether this role is the only one.…”