Article

An adult tissue-specific stem cell in its niche: A gene profiling analysis of in vivo quiescent and activated muscle satellite cells

Molecular Genetics of Development Unit, Department of Developmental Biology, URA CNRS 2578, Institut Pasteur, Paris, France.
Stem Cell Research (Impact Factor: 3.69). 10/2009; 4(2):77-91. DOI: 10.1016/j.scr.2009.10.003
Source: PubMed

ABSTRACT

The satellite cell of skeletal muscle provides a paradigm for quiescent and activated tissue stem cell states. We have carried out transcriptome analyses on satellite cells purified by flow cytometry from Pax3(GFP/+) mice. We compared samples from adult skeletal muscles where satellite cells are mainly quiescent, with samples from growing muscles or regenerating (mdx) muscles, where they are activated. Analysis of regulation that is shared by both activated states avoids other effects due to immature or pathological conditions. This in vivo profile differs from that of previously analyzed satellite cells activated after cell culture. It reveals how the satellite cell protects itself from damage and maintains quiescence, while being primed for activation on receipt of the appropriate signal. This is illustrated by manipulation of the corepressor Dach1, and by the demonstration that quiescent satellite cells are better protected from oxidative stress than those from mdx or 1-week-old muscles. The quiescent versus in vivo activated comparison also gives new insights into how the satellite cell controls its niche on the muscle fiber through cell adhesion and matrix remodeling. The latter also potentiates growth factor activity through proteoglycan modification. Dismantling the extracellular matrix is important for satellite cell activation when the expression of proteinases is up-regulated, whereas transcripts for their inhibitors are high in quiescent cells. In keeping with this, we demonstrate that metalloproteinase function is required for efficient regeneration in vivo.

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Available from: Bertrand Czarny, Jan 12, 2016
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    • "Beside the down-regulation of genes related to the cell cycle and protein translation, entry of NS cells into quiescence is accompanied by the up-regulation of many genes encoding ECM proteins, receptors for ECM molecules, and cell–cell adhesion molecules. This suggests that quiescence involves a profound change in the attachment of NSCs to the ECM and neighboring cells, as previously suggested for NSCs in the adult SEZ (Kazanis et al. 2010; Kokovay et al. 2010, 2012) and for other types of adult stem cells (Venezia et al. 2004; Fukada et al. 2007; Pallafacchina et al. 2010; Brohl et al. 2012). For example, entry of hematopoietic stem cells into quiescence involves homing to their cellular niche, which is mediated by integrins and the transmembrane glycoprotein endoglin (which are significantly induced in quiescent NS cells) (Supplemental Table S1; Venezia et al. 2004). "

    Full-text · Dataset · Sep 2015
    • "The quiescent state appears to be associated with enhanced stress resistance(Gnocchi et al., 2009). Notably, a group of genes that confer resistance to xenobiotics and oxidative stress were found induced during quiescence(Pallafacchina et al., 2010). These include genes that encode efflux channels of the multidrug resistance family that pump toxic substances out of the cell, as well as members of the cytochrome P450 family or flavins, which are involved in the solubilisation of toxins by hydroxylation, and enzymes such as Gpx3, responsible for mitigating reactive oxygen species-mediated cytotoxicity. "
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    ABSTRACT: The skeletal muscle of vertebrates has a huge regenerative capacity. When destroyed after different types of injury, this organ can regenerate very quickly (less than 20 days following myotoxin injection in the mouse) ad integrum and repeatedly. The cell responsible for this regeneration is the so-called satellite cell, the muscle stem cell that lies on top of the muscle fibre, a giant, multinucleated cell that contains the contractile material. When injected in the muscle, satellite cells can efficiently differentiate into contractile muscle fibres. The satellite cell shows great therapeutic potential; and its regenerative capacity has triggered particular interest in the field of muscular degeneration. In this review we will focus on one particular property of the satellite cell: its quiescence and dormancy. Indeed adult satellite cells are quiescent; they lie between the basal lamina and the basement membrane of the muscle fibre, ready to proliferate, and fuse in order to regenerate myofibers upon injury. It has recently been shown that a subpopulation of satellite cells is able to enter dormancy in human and mice cadavers. Dormancy is defined by a low metabolic state, low mobility, and a long lag before division when plated in vitro, compared to quiescent cells. This definition is also based on current knowledge about long-term hematopoietic stem cells, a subpopulation of stem cells that are described as dormant based on the same criteria (rare division and low metabolism when compared to progeny which are dividing more often). In the first part of this review, we will provide a description of satellite cells which addresses their quiescent state. We will then focus on the uneven distribution of satellite cells in the muscle and describe evidence that suggests that their dormancy differs from one muscle to the next and that one should be cautious when making generalisations regarding this cellular state. In a second part, we will discuss the transition between active dividing cells in developing animals to quiescence. This mechanism could be used or amplified in the switch from quiescence to dormancy. In a third part, we will review the signals and dynamics that actively maintain the satellite cell quiescent. The in-depth understanding of these mechanisms is key to describing how dormancy relies on quiescent state of the cells. In a fourth part, we will deal with dormancy per se: how dormant satellite cells can be obtained, their characteristics, their metabolic profile, and their molecular signature as compared to quiescent cells. Here, we will highlight one of the most important recent findings: that quiescence is a prerequisite for the entry of the satellite cell into dormancy. Since dormancy is a newly discovered phenomenon, we will review the mechanisms responsible for quiescence and activation, as these two cellular states are better known and key to understanding satellite cell dormancy. This will allow us to describe dormancy and its prerequisites.
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    • "*p < 0.05 **p < 0.01 ***p < 0.001. activated in EOMs (data not shown) and consistent with observations in TA and other skeletal muscles (Pallafacchina et al., 2010) but in contrast with previous reports in EOMs (McLoon and Wirtschafter, 2002a,b, 2003; McLoon et al., 2004). This likely reflects the different animal species and ages considered (rabbits, mice, rats) as well as the different techniques used to reveal satellite cell activation and proliferation (i.e., single myofiber reconstruction vs. histological analysis of transversal sections) (McLoon and Wirtschafter, 2002a,b; McLoon et al., 2004). "
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    ABSTRACT: Specific muscles are spared in many degenerative myopathies. Most notably, the extraocular muscles (EOMs) do not show clinical signs of late stage myopathies including the accumulation of fibrosis and fat. It has been proposed that an altered stem cell niche underlies the resistance of EOMs in these pathologies, however, to date, no reports have provided a detailed characterization of the EOM stem cell niche. PW1/Peg3 is expressed in progenitor cells in all adult tissues including satellite cells and a subset of interstitial non-satellite cell progenitors in muscle. These PW1-positive interstitial cells (PICs) include a fibroadipogenic progenitor population (FAP) that give rise to fat and fibrosis in late stage myopathies. PICs/FAPs are mobilized following injury and FAPs exert a promyogenic role upon myoblasts in vitro but require the presence of a minimal population of satellite cells in vivo. We and others recently described that FAPs express promyogenic factors while satellite cells express antimyogenic factors suggesting that PICs/FAPs act as support niche cells in skeletal muscle through paracrine interactions. We analyzed the EOM stem cell niche in young adult and aged wild-type mice and found that the balance between PICs and satellite cells within the EOM stem cell niche is maintained throughout life. Moreover, in the adult mdx mouse model for Duchenne muscular dystrophy (DMD), the EOM stem cell niche is unperturbed compared to normal mice, in contrast to Tibialis Anterior (TA) muscle, which displays signs of ongoing degeneration/regeneration. Regenerating mdx TA shows increased levels of both PICs and satellite cells, comparable to normal unaffected EOMs. We propose that the increase in PICs that we observe in normal EOMs contributes to preserving the integrity of the myofibers and satellite cells. Our data suggest that molecular cues regulating muscle regeneration are intrinsic properties of EOMs.
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