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


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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Available from: Malea M Murphy
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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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    ABSTRACT: Background: Abnormal branched myofibers within skeletal muscles are commonly found in diverse animal models of muscular dystrophy as well as in patients. Branched myofibers from dystrophic mice are more susceptible to break than unbranched myofibers suggesting that muscles containing a high percentage of these myofibers are more prone to injury. Previous studies showed ubiquitous over-expression of mouse olfactory receptor 23 (mOR23), a G protein-coupled receptor, in wild type mice decreased myofiber branching. Whether mOR23 over-expression specifically in skeletal muscle cells is sufficient to mitigate myofiber branching in dystrophic muscle is unknown. Methods: We created a novel transgenic mouse over-expressing mOR23 specifically in muscle cells and then bred with dystrophic (mdx) mice. Myofiber branching was analyzed in these two transgenic mice and membrane integrity was assessed by Evans blue dye fluorescence. Results: mOR23 over-expression in muscle led to a decrease of myofiber branching after muscle regeneration in non-dystrophic mouse muscles and reduced the severity of myofiber branching in mdx mouse muscles. Muscles from mdx mouse over-expressing mOR23 significantly exhibited less damage to eccentric contractions than control mdx muscles. Conclusions: The decrease of myofiber branching in mdx mouse muscles over-expressing mOR23 reduced the amount of membrane damage induced by mechanical stress. These results suggest that modifying myofiber branching in dystrophic patients, while not preventing degeneration, could be beneficial for mitigating some of the effects of the disease process.
    Full-text · Article · Dec 2015 · Skeletal Muscle
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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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    ABSTRACT: How resident stem cells and their immediate progenitors rebuild tissues of pre-injury organization and size for proportional regeneration is not well understood. Using 3D, time-lapse intravital imaging for direct visualization of the muscle regeneration process in live mice, we report that extracellular matrix remnants from injured skeletal muscle fibers, "ghost fibers," govern muscle stem/progenitor cell behaviors during proportional regeneration. Stem cells were immobile and quiescent without injury whereas their activated progenitors migrated and divided after injury. Unexpectedly, divisions and migration were primarily bi-directionally oriented along the ghost fiber longitudinal axis, allowing for spreading of progenitors throughout ghost fibers. Re-orienting ghost fibers impacted myogenic progenitors' migratory paths and division planes, causing disorganization of regenerated muscle fibers. We conclude that ghost fibers are autonomous, architectural units necessary for proportional regeneration after tissue injury. This finding reinforces the need to fabricate bioengineered matrices that mimic living tissue matrices for tissue regeneration therapy.
    Full-text · Article · Dec 2015 · Cell stem cell
    • "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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    ABSTRACT: Regeneration of adult tissues depends on somatic stem cells that remain quiescent yet are primed to enter a differentiation program. The molecular pathways that prevent activation of these cells are not well understood. Using mouse skeletal muscle stem cells as a model, we show that a general repression of translation, mediated by the phosphorylation of translation initiation factor eIF2α at serine 51 (P-eIF2α), is required to maintain the quiescent state. Skeletal muscle stem cells unable to phosphorylate eIF2α exit quiescence, activate the myogenic program, and differentiate, but do not self-renew. P-eIF2α ensures in part the robust translational silencing of accumulating mRNAs that is needed to prevent the activation of muscle stem cells. Additionally, P-eIF2α-dependent translation of mRNAs regulated by upstream open reading frames (uORFs) contributes to the molecular signature of stemness. Pharmacological inhibition of eIF2α dephosphorylation enhances skeletal muscle stem cell self-renewal and regenerative capacity.
    No preview · Article · Nov 2015 · Cell stem cell
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