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Thomas A. Rando - One of the best experts on this subject based on the ideXlab platform.
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Mesenchymal Stromal Cells Are Required for Regeneration and Homeostatic Maintenance of Skeletal Muscle
Elsevier, 2019Co-Authors: Michael N. Wosczyna, Qiang Gan, Colin T. Konishi, Edgar Perez E. Carbajal, Theodore T. Wang, Rachel A. Walsh, Mark W. Wagner, Thomas A. RandoAbstract:Summary: The necessity of mesenchymal stromal Cells, called fibroadipogenic progenitors (FAPs), in skeletal Muscle regeneration and maintenance remains unestablished. We report the generation of a PDGFRαCreER knockin mouse model that provides a specific means of labeling and targeting FAPs. Depletion of FAPs using Cre-dependent diphtheria toxin expression results in loss of expansion of Muscle Stem Cells (MuSCs) and CD45+ hematopoietic Cells after injury and impaired skeletal Muscle regeneration. Furthermore, FAP-depleted mice under homeostatic conditions exhibit Muscle atrophy and loss of MuSCs, revealing that FAPs are required for the maintenance of both skeletal Muscle and the MuSC pool. We also report that local tamoxifen metabolite delivery to target CreER activity in a single Muscle, removing potentially confounding syStemic effects of ablating PDGFRα+ Cells distantly, also causes Muscle atrophy. These data establish a critical role of FAPs in skeletal Muscle regeneration and maintenance. : Wosczyna et al. develop genetic models to target and deplete fibroadipogenic progenitors (FAPs) in skeletal Muscle (SkM). Following injury of FAP-depleted SkM, Muscle Stem Cell (MuSC) expansion is impaired, leading to a regenerative deficit. Under homeostatic conditions, FAP-depleted SkM undergoes Muscle fiber atrophy, and MuSC numbers decline. Keywords: Mesenchymal, stromal, fibroadipogenic progenitor, FAP, Muscle, Stem Cell, satellite Cell, niche, PDGFRα, local recombinatio
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a Muscle Stem Cell support group coordinated Cellular responses in Muscle regeneration
Developmental Cell, 2018Co-Authors: Michael N. Wosczyna, Thomas A. RandoAbstract:Skeletal Muscle has an extraordinary regenerative capacity due to the activity of tissue-specific Muscle Stem Cells. Consequently, these Cells have received the most attention in studies investigating the Cellular processes of skeletal Muscle regeneration. However, efficient capacity to rebuild this tissue also depends on additional Cells in the local milieu, as disrupting their normal contributions often leads to incomplete regeneration. Here, we review these additional Cells that contribute to the regenerative process. Understanding the complex interactions between and among these Cell populations has the potential to lead to therapies that will help promote normal skeletal Muscle regeneration under conditions in which this process is suboptimal.
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staufen1 inhibits myod translation to actively maintain Muscle Stem Cell quiescence
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Antoine De Morree, Cindy T J Van Velthoven, Qiang Gan, Jayesh S Salvi, Julian D D Klein, Igor Akimenko, Marco Quarta, Stefano Biressi, Thomas A. RandoAbstract:Tissue regeneration depends on the timely activation of adult Stem Cells. In skeletal Muscle, the adult Stem Cells maintain a quiescent state and proliferate upon injury. We show that Muscle Stem Cells (MuSCs) use direct translational repression to maintain the quiescent state. High-resolution single-molecule and single-Cell analyses demonstrate that quiescent MuSCs express high levels of Myogenic Differentiation 1 (MyoD) transcript in vivo, whereas MyoD protein is absent. RNA pulldowns and costainings show that MyoD mRNA interacts with Staufen1, a potent regulator of mRNA localization, translation, and stability. Staufen1 prevents MyoD translation through its interaction with the MyoD 3'-UTR. MuSCs from Staufen1 heterozygous (Staufen1+/-) mice have increased MyoD protein expression, exit quiescence, and begin proliferating. Conversely, blocking MyoD translation maintains the quiescent phenotype. Collectively, our data show that MuSCs express MyoD mRNA and actively repress its translation to remain quiescent yet primed for activation.
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Macrophage-released ADAMTS1 promotes Muscle Stem Cell activation
Nature communications, 2017Co-Authors: Chung-hsuan Shih, Michael N. Wosczyna, Alisa A. Mueller, Joonseok Cho, Abhishek Aggarwal, Thomas A. Rando, Brian J. FeldmanAbstract:Coordinated activation of Muscle Stem Cells (known as satellite Cells) is critical for postnatal Muscle growth and regeneration. The Muscle Stem Cell niche is central for regulating the activation state of satellite Cells, but the specific extraCellular signals that coordinate this regulation are poorly understood. Here we show that macrophages at sites of Muscle injury induce activation of satellite Cells via expression of Adamts1. Overexpression of Adamts1 in macrophages in vivo is sufficient to increase satellite Cell activation and improve Muscle regeneration in young mice. We demonstrate that NOTCH1 is a target of ADAMTS1 metalloproteinase activity, which reduces Notch signaling, leading to increased satellite Cell activation. These results identify Adamts1 as a potent extraCellular regulator of satellite Cell activation and have significant implications for understanding the regulation of satellite Cell activity and regeneration after Muscle injury.Satellite Cells are crucial for growth and regeneration of skeletal Muscle. Here the authors show that in response to Muscle injury, macrophages secrete Adamts1, which induces satellite Cell activation by modulating Notch1 signaling.
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induction of autophagy supports the bioenergetic demands of quiescent Muscle Stem Cell activation
The EMBO Journal, 2014Co-Authors: Ann H Tang, Thomas A. RandoAbstract:The exit of a Stem Cell out of quiescence into an activated state is characterized by major metabolic changes associated with increased biosynthesis of proteins and macromolecules. The regulation of this transition is poorly understood. Using Muscle Stem Cells, or satellite Cells (SCs), we found that autophagy, which catabolizes intraCellular contents to maintain proteostasis and to produce energy during nutrient deprivation, was induced during SC activation. Inhibition of autophagy suppressed the increase in ATP levels and delayed SC activation, both of which could be partially rescued by exogenous pyruvate as an energy source, suggesting that autophagy may provide nutrients necessary to meet bioenergetic demands during this critical transition from quiescence to activation. We found that SIRT1, a known nutrient sensor, regulates autophagic flux in SC progeny. A deficiency of SIRT1 led to a delay in SC activation that could also be partially rescued by exogenous pyruvate. These studies suggest that autophagy, regulated by SIRT1, may play an important role during SC activation to meet the high bioenergetic demands of the activation process.
Helen M. Blau - One of the best experts on this subject based on the ideXlab platform.
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Glucose Metabolism Drives Histone Acetylation Landscape Transitions that Dictate Muscle Stem Cell Function
Cell Reports, 2019Co-Authors: Nora Yucel, Ermelinda Porpiglia, Yu Xin Wang, Benjamin A. Garcia, Thach Mai, Peder J. Lund, Glenn J. Markov, Sean C. Bendall, Michael Angelo, Helen M. BlauAbstract:Summary The impact of glucose metabolism on Muscle regeneration remains unresolved. We identify glucose metabolism as a crucial driver of histone acetylation and myogenic Cell fate. We use single-Cell mass cytometry (CyTOF) and flow cytometry to characterize the histone acetylation and metabolic states of quiescent, activated, and differentiating Muscle Stem Cells (MuSCs). We find glucose is dispensable for mitochondrial respiration in proliferating MuSCs, so that glucose becomes available for maintaining high histone acetylation via acetyl-CoA. Conversely, quiescent and differentiating MuSCs increase glucose utilization for respiration and have consequently reduced acetylation. Pyruvate dehydrogenase (PDH) activity serves as a rheostat for histone acetylation and must be controlled for Muscle regeneration. Increased PDH activity in proliferation increases histone acetylation and chromatin accessibility at genes that must be silenced for differentiation to proceed, and thus promotes self-renewal. These results highlight metabolism as a determinant of MuSC histone acetylation, fate, and function during Muscle regeneration.
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Prostaglandin E2 is essential for efficacious skeletal Muscle Stem-Cell function, augmenting regeneration and strength
Proceedings of the National Academy of Sciences, 2017Co-Authors: Andrew T. V. Ho, Adelaida R. Palla, Matthew R. Blake, Nora D. Yucel, Colin A. Holbrook, Yu Xin Wang, Klas E G Magnusson, Peggy E Kraft, Scott L. Delp, Helen M. BlauAbstract:Skeletal Muscles harbor quiescent Muscle-specific Stem Cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of Cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment Muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased Muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises Muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1 Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes Muscle repair and strength. Through such gain- or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for Muscle Stem-Cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged Muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent.
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Noninvasive Tracking of Quiescent and Activated Muscle Stem Cell (MuSC) Engraftment Dynamics In Vivo.
Methods in molecular biology (Clifton N.J.), 2016Co-Authors: Andrew Tri Van Ho, Helen M. BlauAbstract:Muscle Stem Cells play a central role in Muscle regeneration. Most studies in the field of Muscle regeneration focus on the unraveling of Muscle Stem Cell biology to devise strategies for treating failing Muscles as seen in aging and Muscle-related diseases. However, the common method used in assessing Stem Cell function in vivo is laborious, as it involves time-consuming immunohistological analyses by microscopy on serial cryo-sections of the Muscle post Stem Cell transplantation. Here we describe an alternative method, which adapts the bioluminescence imaging (BLI) technique to allow noninvasive tracking of engrafted Stem-Cell function in vivo in real-time. This assay syStem enables longitudinal studies in the same mice over time and reveals parameters, not feasible by traditional analysis, such as the magnitude and dynamics of engrafted Muscle Stem Cell expansion in vivo in response to a particular drug treatment or Muscle injury.
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The aging Muscle Stem Cell niche as a therapeutic target (79.2)
The FASEB Journal, 2014Co-Authors: Penney M Gilbert, Benjamin D Cosgrove, Neeraj Gupta, Helen M. BlauAbstract:Impaired Muscle strength and regeneration are major problems of aging. We found that skeletal Muscle Stem Cells (MuSCs) from aged mice are two-thirds less effective in regenerating Muscle than young MuSCs, even in a young microenvironment. Culture of aged MuSCs in hydrogel niches in conjunction with a pharmacological inhibitor of p38 mitogen-activated protein kinase, enhanced MuSC proliferation and decreased the proportion expressing p16Ink4a. The capacity of this population to regenerate damaged Muscles was similar to young MuSCs following transplantation into mice, evaluated by non-invasive imaging, Stem-Cell repopulation, and serial transplantation assays. The rejuvenation of the aged Muscle Stem Cell population was attributable to expansion of a functional subpopulation, as revealed by time-lapse microscopy. Molecular analyses identified a mechanism whereby substrate mechanics contributes to the modulation of MuSC Stemness. Notably, strength was restored when the rejuvenated population was delivered t...
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Rejuvenation of the Muscle Stem Cell population restores strength to injured aged Muscles
Nature Medicine, 2014Co-Authors: Benjamin D Cosgrove, Ermelinda Porpiglia, Steven P. Lee, Michael E. Llewellyn, Foteini Mourkioti, Stephane Y Corbel, Penney M Gilbert, Scott L. Delp, Helen M. BlauAbstract:The elderly often suffer from progressive Muscle weakness and regenerative failure. We demonstrate that Muscle regeneration is impaired with aging owing in part to a Cell-autonomous functional decline in skeletal Muscle Stem Cells (MuSCs). Two-thirds of MuSCs from aged mice are intrinsically defective relative to MuSCs from young mice, with reduced capacity to repair myofibers and repopulate the Stem Cell reservoir in vivo following transplantation. This deficiency is correlated with a higher incidence of Cells that express senescence markers and is due to elevated activity of the p38α and p38β mitogen-activated kinase pathway. We show that these limitations cannot be overcome by transplantation into the microenvironment of young recipient Muscles. In contrast, subjecting the MuSC population from aged mice to transient inhibition of p38α and p38β in conjunction with culture on soft hydrogel substrates rapidly expands the residual functional MuSC population from aged mice, rejuvenating its potential for regeneration and serial transplantation as well as strengthening of damaged Muscles of aged mice. These findings reveal a synergy between biophysical and biochemical cues that provides a paradigm for a localized autologous Muscle Stem Cell therapy for the elderly.
Michael A. Rudnicki - One of the best experts on this subject based on the ideXlab platform.
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The Dystrophin Glycoprotein Complex Regulates the Epigenetic Activation of Muscle Stem Cell Commitment.
Cell stem cell, 2018Co-Authors: Natasha C. Chang, Pura Muñoz-cánoves, Marie Claude Sincennes, Fabien P. Chevalier, Caroline E. Brun, Melanie Lacaria, Jessica Segalés, Hong Ming, Michael A. RudnickiAbstract:Summary Asymmetrically dividing Muscle Stem Cells in skeletal Muscle give rise to committed Cells, where the myogenic determination factor Myf5 is transcriptionally activated by Pax7. This activation is dependent on Carm1, which methylates Pax7 on multiple arginine residues, to recruit the ASH2L:MLL1/2:WDR5:RBBP5 histone methyltransferase complex to the proximal promoter of Myf5 . Here, we found that Carm1 is a specific substrate of p38γ/MAPK12 and that phosphorylation of Carm1 prevents its nuclear translocation. Basal localization of the p38γ/p-Carm1 complex in Muscle Stem Cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient Muscle Stem Cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation. The resulting progenitors exhibit reduced Carm1 binding to Pax7, reduced H3K4-methylation of chromatin, and reduced transcription of Myf5 and other Pax7 target genes. Therefore, our experiments suggest that dysregulation of p38γ/Carm1 results in altered epigenetic gene regulation in Duchenne muscular dystrophy.
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Targeting Muscle Stem Cell intrinsic defects to treat Duchenne muscular dystrophy
npj Regenerative Medicine, 2016Co-Authors: Nicolas A Dumont, Michael A. RudnickiAbstract:Duchenne muscular dystrophy (DMD) is a genetic disease characterised by skeletal Muscle degeneration and progressive Muscle wasting, which is caused by loss-of-function mutations in the DMD gene that encodes for the protein dystrophin. Dystrophin has critical roles in myofiber stability and integrity by connecting the actin cytoskeleton to the extraCellular matrix. Absence of dystrophin leads to myofiber fragility and contributes to skeletal Muscle degeneration in DMD patients, however, accumulating evidence also indicate that Muscle Stem Cells (also known as satellite Cells) are defective in dystrophic Muscles, which leads to impaired Muscle regeneration. Our recent work demonstrated that dystrophin is expressed in activated satellite Cells, where it regulates the establishment of satellite Cell polarity and asymmetric Cell division. These findings indicate that dystrophin-deficient satellite Cells have intrinsic dysfunctions that contribute to Muscle wasting and progression of the disease. This discovery suggests that satellite Cells could be targeted to treat DMD. Here we discuss how these new findings affect regenerative therapies for muscular dystrophies. Therapies targeting satellite Cells hold great potential and could have long-term efficiency owing to the high self-renewal ability of these Cells.
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Rejuvenating aged Muscle Stem Cells
Nature medicine, 2014Co-Authors: C. Florian Bentzinger, Michael A. RudnickiAbstract:Decreased Muscle Stem Cell function in aging has long been shown to depend on altered environmental cues, whereas the contribution of intrinsic mechanisms remained less clear. Two new studies now reveal that Cell-autonomous changes in the p38 mitogen-activated protein kinase pathway are major phenotype determinants of aged Muscles Stem Cells (pages 255 – 271 ).
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satellite Cells and the Muscle Stem Cell niche
Physical Review, 2013Co-Authors: Hang Yin, Feodor D Price, Michael A. RudnickiAbstract:Adult skeletal Muscle in mammals is a stable tissue under normal circumstances but has remarkable ability to repair after injury. Skeletal Muscle regeneration is a highly orchestrated process involving the activation of various Cellular and molecular responses. As skeletal Muscle Stem Cells, satellite Cells play an indispensible role in this process. The self-renewing proliferation of satellite Cells not only maintains the Stem Cell population but also provides numerous myogenic Cells, which proliferate, differentiate, fuse, and lead to new myofiber formation and reconstitution of a functional contractile apparatus. The complex behavior of satellite Cells during skeletal Muscle regeneration is tightly regulated through the dynamic interplay between intrinsic factors within satellite Cells and extrinsic factors constituting the Muscle Stem Cell niche/microenvironment. For the last half century, the advance of molecular biology, Cell biology, and genetics has greatly improved our understanding of skeletal Muscle biology. Here, we review some recent advances, with focuses on functions of satellite Cells and their niche during the process of skeletal Muscle regeneration.
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satellite Cells and the Muscle Stem Cell niche
Physiological Reviews, 2013Co-Authors: Feodor D Price, Michael A. RudnickiAbstract:Adult skeletal Muscle in mammals is a stable tissue under normal circumstances but has remarkable ability to repair after injury. Skeletal Muscle regeneration is a highly orchestrated process invol...
Shahragim Tajbakhsh - One of the best experts on this subject based on the ideXlab platform.
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Distinct metabolic states govern skeletal Muscle Stem Cell fates during prenatal and postnatal myogenesis
Journal of Cell Science, 2018Co-Authors: Francesca Pala, Miria Ricchetti, Daniela Di Girolamo, Sébastien Mella, Siham Yennek, Laurent Chatre, Shahragim TajbakhshAbstract:During growth, homeostasis and regeneration, Stem Cells are exposed to different energy demands. Here, we characterise the metabolic pathways that mediate the commitment and differentiation of mouse skeletal Muscle Stem Cells, and how their modulation can influence the Cell state. We show that quiescent satellite Stem Cells have low energetic demands and perturbed oxidative phosphorylation during ageing, which is also the case for Cells from post-mortem tissues. We show also that myogenic fetal Cells have distinct metabolic requirements compared to those proliferating during regeneration, with the former displaying a low respiration demand relying mostly on glycolysis. Furthermore, we show distinct requirements for peroxisomal and mitochondrial fatty acid oxidation (FAO) in myogenic Cells. Compromising peroxisomal but not mitochondrial FAO promotes early differentiation of myogenic Cells. Acute Muscle injury and pharmacological block of peroxisomal and mitochondrial FAO expose differential requirements for these organelles during Muscle regeneration. Taken together, these observations indicate that changes in myogenic Cell state lead to significant alterations in metabolic requirements. In addition, perturbing specific metabolic pathways impacts on myogenic Cell fates and the regeneration process.
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Skeletal Muscle Stem Cell birth and properties.
Seminars in cell & developmental biology, 2007Co-Authors: Ramkumar Sambasivan, Shahragim TajbakhshAbstract:Development and maintenance of an abundant tissue such as skeletal Muscle poses several challenges. Curiously, not all skeletal Muscle Stem Cells are born alike, since diverse genetic pathways can specify their birth. Stem and progenitor Cells that establish the tissue during development, those that maintain its homeostasis, as well as participate in its regeneration have generated considerable interest. The ability to distinguish Stem Cells from more committed progenitors throughout prenatal and postnatal life has guided researchers to identify Stem Cell properties and characterise their niche. These properties include markers that influence Cell behaviour and mode of division during normal development, after trauma and Cell transplantations. This review addresses these issues from a developmental perspective.
Bradley B Olwin - One of the best experts on this subject based on the ideXlab platform.
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Transplantation of Skeletal Muscle Stem Cells.
Methods in molecular biology (Clifton N.J.), 2017Co-Authors: Monica N. Hall, Jason D. Doles, John K. Hall, Adam B. Cadwallader, Bradley Pawlikowski, Tiffany L. Elston, Bradley B OlwinAbstract:Transplanting adult Stem Cells provides a stringent test for self-renewal and the assessment of comparative engraftment in competitive transplant assays. Transplantation of satellite Cells into mammalian skeletal Muscle provided the first critical evidence that satellite Cells function as adult Muscle Stem Cells. Transplantation of a single satellite Cell confirmed and extended this hypothesis, providing proof that the satellite Cell is a bona fide adult skeletal Muscle Stem Cell as reported by Sacco et al. (Nature 456(7221):502-506). Satellite Cell transplantation has been further leveraged to identify culture conditions that maintain engraftment and to identify self-renewal deficits in satellite Cells from aged mice. Conversion of iPSCs (induced pluripotent Stem Cells) to a satellite Cell-like state, followed by transplantation, demonstrated that these Cells possess adult Muscle Stem Cell properties as reported by Darabi et al. (Stem Cell Rev Rep 7(4):948-957) and Mizuno et al. (FASEB J 24(7):2245-2253). Thus, transplantation strategies involving either satellite Cells derived from adult Muscles or derived from iPSCs may eventually be exploited as a therapy for treating patients with diseased or failing skeletal Muscle. Here, we describe methods for isolating dispersed adult mouse satellite Cells and satellite Cells on intact myofibers for transplantation into recipient mice to study Muscle Stem Cell function and behavior following engraftment .
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Loss of niche-satellite Cell interactions in syndecan-3 null mice alters Muscle progenitor Cell homeostasis improving Muscle regeneration.
Skeletal Muscle, 2016Co-Authors: Addolorata Pisconti, Glen B. Banks, Farshad Babaeijandaghi, Nicole Dalla Betta, Fabio M.v. Rossi, Jeffrey S. Chamberlain, Bradley B OlwinAbstract:Background The skeletal Muscle Stem Cell niche provides an environment that maintains quiescent satellite Cells, required for skeletal Muscle homeostasis and regeneration. Syndecan-3, a transmembrane proteoglycan expressed in satellite Cells, supports communication with the niche, providing Cell interactions and signals to maintain quiescent satellite Cells.
