Article

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

Department of Human Genetics, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA.
Development (Impact Factor: 6.46). 09/2011; 138(17):3625-37. DOI: 10.1242/dev.064162
Source: PubMed

ABSTRACT

Muscle 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 Pax7(CreERT2) 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.

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    • "Mouse muscles electroporated with a plasmid expressing mOR23 under the control of a ubiquitous promoter contained fewer branched myofibers and fewer branches per myofiber[7]. In the skeletal muscle, several types of cells are important for muscle regeneration such as neutrophils[12], macrophages[13], and fibroblasts[14]in addition to muscle stem cells[15]. Since mOR23 was ubiquitously over-expressed, whether mOR23 was required specifically in muscle cells to regulate myofiber branching could not be addressed in these experiments. "
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    • "Muscle stem cells and their descendant myogenic progenitors possess great therapeutic potential for regenerating muscle following traumatic injury and muscle disease, yet insight into muscle stem cell/progenitor behavior during injury-induced regeneration is incomplete. Residing between the sarcolemma and basal lamina of myofibers (Figure 1A), Pax7-expressing (Pax7+) satellite cells (SCs) are the principal resident stem cells directly contributing to muscle regeneration in mice (Lepper et al., 2009, 2011; McCarthy et al., 2011; Murphy et al., 2011). "
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    • "Adult tissues with regenerative potential harbor stem cells that are primed to enter a differentiation program while remaining quiescent (Simons and Clevers, 2011). These properties are illustrated by skeletal muscle stem cells, which are named ''satellite cells'' for their position underneath the basal lamina of myofibers (Mauro, 1961) and are essential for all post-natal growth and repair of skeletal muscle (Lepper et al., 2011; McCarthy et al., 2011; Murphy et al., 2011; Sambasivan et al., 2011). Satellite cells and the skeletal muscle progenitor cells that are present during development commonly express members of the paired homeodomain family of transcription factors, Pax3 and/or Pax7 (Relaix et al., 2006). "
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