Satellite cell

卫星小区
  • 文章类型: Journal Article
    已经证明,caspase3活性是骨骼肌再生所必需的,但是它的活动是如何调节的,在很大程度上是未知的。我们以前的报告显示,细胞内TMEM16A,钙激活的氯化物通道,在骨骼肌发育过程中显着调节成肌细胞的caspase3活性。通过使用具有TMEM16A卫星细胞(SC)特异性缺失的小鼠系,我们研究了TMEM16A在调节SC(或SC衍生的成肌细胞)以及骨骼肌再生中的caspase3活性中的作用。突变动物在成年肌肉中表现出明显受损的再生能力,同时在Tmem16a-/-SC衍生的成肌细胞中ER应激增强和caspase3活性升高。通过小分子阻断过度的内质网应激或半胱天冬酶3活性显着恢复被抑制的Tmem16a-/-SCs的成肌分化,表明TMEM16A缺失导致的caspase3活性过高导致肌肉再生受损,caspase3的上游调节因子是ER应激。我们的结果表明,通过确保中等水平的caspase3活性,TMEM16A在卫星细胞介导的骨骼肌再生中具有重要作用。
    It has been documented that caspase 3 activity is necessary for skeletal muscle regeneration, but how its activity is regulated is largely unknown. Our previous report shows that intracellular TMEM16A, a calcium activated chloride channel, significantly regulates caspase 3 activity in myoblasts during skeletal muscle development. By using a mouse line with satellite cell (SC)-specific deletion of TMEM16A, we examined the role of TMEM16A in regulating caspase 3 activity in SC (or SC-derived myoblast) as well as skeletal muscle regeneration. The mutant animals displayed apparently impaired regeneration capacity in adult muscle along with enhanced ER stress and elevated caspase 3 activity in Tmem16a-/- SC derived myoblasts. Blockade of either excessive ER stress or caspase 3 activity by small molecules significantly restored the inhibited myogenic differentiation of Tmem16a-/- SCs, indicating that excessive caspase 3 activity resulted from TMEM16A deletion contributes to the impaired muscle regeneration and the upstream regulator of caspase 3 was ER stress. Our results revealed an essential role of TMEM16A in satellite cell mediated skeletal muscle regeneration by ensuring a moderate level of caspase 3 activity.
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  • 文章类型: Journal Article
    骨骼肌在受伤时经历强大的再生,浸润的免疫细胞不仅在清除受损组织中起主要作用,而且还通过分泌的细胞因子调节成肌过程。趋化因子C-C基序配体8(Ccl8),已报道与Ccl2和Ccl7一起介导炎症反应以抑制肌肉再生。Ccl8也由肌肉细胞表达,但是肌肉细胞来源的Ccl8在肌生成中的作用尚未被报道。在这项研究中,我们发现,敲除Ccl8,而不是Ccl2或Ccl7,导致C2C12成肌细胞分化增加。对现有单细胞转录组数据集的分析显示,再生肌肉中的免疫细胞和肌肉干细胞(MuSC)都表达Ccl8,而MuSC的表达水平要低得多。CCl8表达的时间模式在MuSCs和巨噬细胞中不同。为了探索肌细胞来源的Ccl8在体内的功能,我们使用了一个小鼠系统,其中Cas9在Pax7+生肌祖细胞(MPCs)中表达,Ccl8基因编辑由AAV9递送的sgRNA诱导.Pax7MPCs中Ccl8的消耗导致年轻和中年小鼠氯化钡诱导的损伤后肌肉再生加速,和肌内施用重组Ccl8逆转了表型。当通过类似方法在Myf5+或MyoD+MPC中耗尽Ccl8时,也观察到加速再生。我们的结果表明,肌细胞来源的Ccl8在调节损伤诱导的肌肉再生过程中肌源性分化的启动中起着独特的作用。
    Skeletal muscles undergo robust regeneration upon injury, and infiltrating immune cells play a major role in not only clearing damaged tissues but also regulating the myogenic process through secreted cytokines. Chemokine C-C motif ligand 8 (Ccl8), along with Ccl2 and Ccl7, has been reported to mediate inflammatory responses to suppress muscle regeneration. Ccl8 is also expressed by muscle cells, but a role of the muscle cell-derived Ccl8 in myogenesis has not been reported. In this study, we found that knockdown of Ccl8, but not Ccl2 or Ccl7, led to increased differentiation of C2C12 myoblasts. Analysis of existing single-cell transcriptomic datasets revealed that both immune cells and muscle stem cells (MuSCs) in regenerating muscles express Ccl8, with the expression by MuSCs at a much lower level, and that the temporal patterns of Ccl8 expression were different in MuSCs and macrophages. To probe a function of muscle cell-derived Ccl8 in vivo, we utilized a mouse system in which Cas9 was expressed in Pax7+ myogenic progenitor cells (MPCs) and Ccl8 gene editing was induced by AAV9-delivered sgRNA. Depletion of Ccl8 in Pax7+ MPCs resulted in accelerated muscle regeneration after barium chloride-induced injury in both young and middle-aged mice, and intramuscular administration of a recombinant Ccl8 reversed the phenotype. Accelerated regeneration was also observed when Ccl8 was depleted in Myf5+ or MyoD+ MPCs by similar approaches. Our results suggest that muscle cell-derived Ccl8 plays a unique role in regulating the initiation of myogenic differentiation during injury-induced muscle regeneration.
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  • 文章类型: Journal Article
    骨骼肌是再生能力最高的组织之一,一个精细控制的过程,关键取决于肌肉干细胞。肌肉干细胞功能取决于内在信号通路和与其直接生态位的相互作用。受伤后,静止的肌肉干细胞被激活,增殖并融合形成新的肌纤维,涉及骨骼肌再生中多种细胞类型相互作用的过程。肌肉干细胞中的受体通过直接的细胞-细胞相互作用接收各自的信号,通过分泌因子或细胞-基质相互作用的信号传导,从而调节肌肉干细胞对外部刺激的反应。这里,我们讨论了肌肉干细胞如何与它们的直接生态位相互作用,重点是如何控制它们的静止,激活和自我更新,以及这些过程如何在年龄和疾病中改变。
    Skeletal muscle is one of the tissues with the highest ability to regenerate, a finely controlled process which is critically depending on muscle stem cells. Muscle stem cell functionality depends on intrinsic signaling pathways and interaction with their immediate niche. Upon injury quiescent muscle stem cells get activated, proliferate and fuse to form new myofibers, a process involving the interaction of multiple cell types in regenerating skeletal muscle. Receptors in muscle stem cells receive the respective signals through direct cell-cell interaction, signaling via secreted factors or cell-matrix interactions thereby regulating responses of muscle stem cells to external stimuli. Here, we discuss how muscle stem cells interact with their immediate niche focusing on how this controls their quiescence, activation and self-renewal and how these processes are altered in age and disease.
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  • 文章类型: Journal Article
    离体肌纤维培养系统已被证明是探索卫星细胞在其生态位环境中的生物学和行为的有用方法。然而,该系统的局限性在于,肌纤维及其相关的卫星细胞通常使用常规的荧光显微镜检查,将三维系统转化为二维成像,导致宝贵信息的丢失或对观察结果的误导性解释。这里,我们报告了使用光片荧光显微镜对肌纤维上的卫星细胞进行三维和活体成像。光片显微镜提供高成像速度和良好的空间分辨率与最小的光漂白,允许实时成像和骨骼肌纤维标本的三维采集。这项技术的潜力很大,从卫星细胞行为(如细胞分裂和细胞迁移)的可视化到蛋白质或细胞器的亚细胞定位成像。
    The ex vivo myofiber culture system has proven to be a useful methodology to explore the biology and behavior of satellite cells within their niche environment. However, a limitation of this system is that myofibers and their associated satellite cells are commonly examined using conventional fluorescence microscopy, which renders a three-dimensional system into two-dimensional imaging, leading to the loss of precious information or misleading interpretation of observations. Here, we report on the use of light-sheet fluorescence microscopy to generate three-dimensional and live imaging of satellite cells on myofibers. Light-sheet microscopy offers high imaging speed and good spatial resolution with minimal photo-bleaching, allowing live imaging and three-dimensional acquisition of skeletal muscle fiber specimen. The potentials of this technology are wide, ranging from the visualization of satellite cell behavior such as cell division and cell migration to imaging the sub-cellular localization of proteins or organelles.
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  • 文章类型: Journal Article
    股四头肌在膝骨关节炎(OA)的进展和症状表现中起着关键作用,特别是疼痛。这项研究调查了肌肉增强和支持疗法(MEST)的治疗效果,一种最近开发的用于肌内插入cog聚二恶烷酮细丝的装置,在股四头肌修复中缓解OA疼痛。通过单碘乙酸盐注射在SpragueDawley大鼠中诱导膝关节OA。在OA或幼稚大鼠股四头肌中进行MEST或假治疗。使用爪退缩阈值和负重来评估疼痛。使用生物标志物评估股四头肌损伤和通过MEST恢复,组织形态学,肌肉质量,收缩力和后肢扭矩。卫星细胞和巨噬细胞活化,以及他们的活化剂,也进行了评估。在MEST治疗后1周和3周比较数据(M-W1和M-W3)。MEST治疗OA大鼠引起的肌肉损伤,血清天冬氨酸转移酶和肌酐激酶水平升高,和M-W1处的局部β-肌动蛋白变化。这种损伤引发了促炎巨噬细胞和卫星细胞活化,伴随着白细胞介素-6和胰岛素样生长因子-1水平升高。然而,通过M-W3,这些过程逐渐转向炎症消退和肌肉恢复。这在抗炎巨噬细胞表型中可见,持续的卫星细胞活化和损伤标志物回归基线。在M-W3时,股四头肌从萎缩中恢复的质量和力量与显著减轻OA疼痛相关。这项研究表明,MEST诱导的轻微肌肉损伤会触发巨噬细胞和卫星细胞激活,导致OA大鼠股四头肌萎缩恢复和疼痛缓解。
    Quadriceps muscles play a pivotal role in knee osteoarthritis (OA) progression and symptom manifestation, particularly pain. This research investigates the therapeutic effectiveness of muscle enhancement and support therapy (MEST), a recently developed device intended for intramuscular insertion of cog polydioxanone filaments, in quadriceps restoration to alleviate OA pain. Knee OA was induced in Sprague Dawley rats via monoiodoacetate injections. MEST or sham treatment was performed in OA or Naive rat quadriceps. Pain was assessed using paw withdrawal threshold and weight bearing. Quadriceps injury and recovery via MEST were evaluated using biomarkers, tissue morphology, muscle mass, contractile force and hindlimb torque. Satellite cell and macrophage activation, along with their activators, were also assessed. Data were compared at 1- and 3-weeks post-MEST treatment (M-W1 and M-W3). MEST treatment in OA rats caused muscle injury, indicated by elevated serum aspartate transferase and creatinine kinase levels, and local β-actin changes at M-W1. This injury triggered pro-inflammatory macrophage and satellite cell activation, accompanied by heightened interleukin-6 and insulin-like growth factor-1 levels. However, by M-W3, these processes gradually shifted toward inflammation resolution and muscle restoration. This was seen in anti-inflammatory macrophage phenotypes, sustained satellite cell activation and injury markers regressing to baseline. Quadriceps recovery in mass and strength from atrophy correlated with substantial OA pain reduction at M-W3. This study suggests that MEST-induced minor muscle injury triggers macrophage and satellite cell activation, leading to recovery of atrophied quadriceps and pain relief in OA rats.
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  • 文章类型: Journal Article
    内皮和骨骼肌谱系产生于常见的胚胎祖细胞。尽管他们共同的发展起源,成人内皮细胞(ECs)和肌肉干细胞(MuSCs)(卫星细胞)被认为具有不同的基因特征和信号通路.在这里,我们通过揭示成年MuSC行为如何受到EC转录本子集表达的影响来改变这种范式。我们使用了几种计算分析,包括单细胞RNAseq,以显示MuSC在小鼠中表达低水平的经典EC标记。我们证明了MuSC的存活受一个这样的原型内皮信号通路(VEGFA-FLT1)的调节。使用药理学和遗传功能增益和丧失研究,我们确定FLT1-AKT1轴是VEGFA介导的MuSC存活调节的关键效应子.一起,我们的数据支持VEGFA-FLT1-AKT1途径促进肌肉再生过程中的MuSC存活,并强调了选择转录物的次要表达如何足以影响细胞行为。
    Endothelial and skeletal muscle lineages arise from common embryonic progenitors. Despite their shared developmental origin, adult endothelial cells (ECs) and muscle stem cells (MuSCs; satellite cells) have been thought to possess distinct gene signatures and signaling pathways. Here, we shift this paradigm by uncovering how adult MuSC behavior is affected by the expression of a subset of EC transcripts. We used several computational analyses including single-cell RNA-seq (scRNA-seq) to show that MuSCs express low levels of canonical EC markers in mice. We demonstrate that MuSC survival is regulated by one such prototypic endothelial signaling pathway (VEGFA-FLT1). Using pharmacological and genetic gain- and loss-of-function studies, we identify the FLT1-AKT1 axis as the key effector underlying VEGFA-mediated regulation of MuSC survival. All together, our data support that the VEGFA-FLT1-AKT1 pathway promotes MuSC survival during muscle regeneration, and highlights how the minor expression of select transcripts is sufficient for affecting cell behavior.
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  • 文章类型: Journal Article
    由各种各样的细胞组成,骨骼肌是人体损伤后具有显著再生能力的组织之一。再生过程中的关键参与者之一是肌肉卫星细胞(MuSC),骨骼肌干细胞群,因为它是新肌纤维的来源。在稳态期间维持MuSC静止涉及MuSC与成年骨骼肌中相应小生境中的其他细胞之间的复杂相互作用。受伤后,MuSCs被激活进入细胞周期进行细胞增殖并分化为肌管,然后是成熟的肌纤维再生肌肉。尽管经过几十年的研究,MuSC维持和激活的确切机制仍然难以捉摸。分析MuSCs的传统方法,包括细胞培养,动物模型,和基因表达分析,提供对MuSC生物学的一些见解,但缺乏复制3维(3-D)体内肌肉环境和全面捕获动态过程的能力。成像技术的最新进展,包括共焦,活体内,和多光子显微镜,为观察和表征动态MuSC形态和行为提供了有希望的途径。本章旨在回顾3-D和实时成像方法,这些方法有助于发现对MuSC行为的见解,形态变化,肌肉小生境内的相互作用,和在静止到激活(Q-A)过渡期间的内部信号通路。整合先进的成像模式和计算工具为研究骨骼肌再生和肌肉退行性疾病(例如肌肉减少症和杜氏肌营养不良症(DMD))中的复杂生物学过程提供了新的途径。
    Composed of a diverse variety of cells, the skeletal muscle is one of the body\'s tissues with the remarkable ability to regenerate after injury. One of the key players in the regeneration process is the muscle satellite cell (MuSC), a stem cell population for skeletal muscle, as it is the source of new myofibers. Maintaining MuSC quiescence during homeostasis involves complex interactions between MuSCs and other cells in their corresponding niche in adult skeletal muscle. After the injury, MuSCs are activated to enter the cell cycle for cell proliferation and differentiate into myotubes, followed by mature myofibers to regenerate muscle. Despite decades of research, the exact mechanisms underlying MuSC maintenance and activation remain elusive. Traditional methods of analyzing MuSCs, including cell cultures, animal models, and gene expression analyses, provide some insight into MuSC biology but lack the ability to replicate the 3-dimensional (3-D) in vivo muscle environment and capture dynamic processes comprehensively. Recent advancements in imaging technology, including confocal, intra-vital, and multi-photon microscopies, provide promising avenues for dynamic MuSC morphology and behavior to be observed and characterized. This chapter aims to review 3-D and live-imaging methods that have contributed to uncovering insights into MuSC behavior, morphology changes, interactions within the muscle niche, and internal signaling pathways during the quiescence to activation (Q-A) transition. Integrating advanced imaging modalities and computational tools provides a new avenue for studying complex biological processes in skeletal muscle regeneration and muscle degenerative diseases such as sarcopenia and Duchenne muscular dystrophy (DMD).
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  • 文章类型: Journal Article
    生肌再生依赖于卫星细胞的增殖和分化。TECRL(反式-2,3-烯酰-CoA还原酶样)是仅在心肌和骨骼肌中表达的内质网蛋白。然而,其在肌生成中的作用尚不清楚。我们显示TECRL表达响应于损伤而增加。TECRL的卫星细胞特异性缺失通过激活ERK1/2信号通路增加EGR2的表达来增强肌肉修复,进而促进PAX7的表达。我们进一步表明,TECRL缺失导致组蛋白乙酰转移酶一般控制不可去抑制的5上调,从而通过乙酰化增强EGR2的转录。重要的是,我们发现AAV9介导的TECRL沉默能改善小鼠的肌肉修复。这些发现揭示了肌源性再生和肌肉修复。
    Myogenic regeneration relies on the proliferation and differentiation of satellite cells. TECRL (trans-2,3-enoyl-CoA reductase like) is an endoplasmic reticulum protein only expressed in cardiac and skeletal muscle. However, its role in myogenesis remains unknown. We show that TECRL expression is increased in response to injury. Satellite cell-specific deletion of TECRL enhances muscle repair by increasing the expression of EGR2 through the activation of the ERK1/2 signaling pathway, which in turn promotes the expression of PAX7. We further show that TECRL deletion led to the upregulation of the histone acetyltransferase general control nonderepressible 5, which enhances the transcription of EGR2 through acetylation. Importantly, we showed that AAV9-mediated TECRL silencing improved muscle repair in mice. These findings shed light on myogenic regeneration and muscle repair.
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  • 文章类型: Journal Article
    最近的研究强调了分子昼夜节律机制在调节组织特异性功能和应激反应中的重要作用。的确,昼夜节律功能的中断,这在现代社会普遍存在,与加速衰老有关,肥胖,和2型糖尿病。此外,最近有证据表明,成熟肌肉组织和卫星细胞内的生物钟对调节肌肉质量的维持和响应损伤的修复能力的重要性。这里,我们回顾了卫星细胞(也称为成年肌肉干细胞)中昼夜节律时钟的发现,以及它们如何调节新陈代谢,表观遗传学,和健康和疾病状态下的肌生成。
    Recent research has highlighted an important role for the molecular circadian machinery in the regulation of tissue-specific function and stress responses. Indeed, disruption of circadian function, which is pervasive in modern society, is linked to accelerated aging, obesity, and type 2 diabetes. Furthermore, evidence supporting the importance of the circadian clock within both the mature muscle tissue and satellite cells to regulate the maintenance of muscle mass and repair capacity in response injury has recently emerged. Here, we review the discovery of circadian clocks within the satellite cell (a.k.a. adult muscle stem cell) and how they act to regulate metabolism, epigenetics, and myogenesis during both healthy and diseased states.
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  • 文章类型: Journal Article
    卫星细胞,以它们在肌纤维肌膜周围的卫星位置命名,负责骨骼肌再生。卫星细胞通常处于静止状态,但迅速激活生肌程序和细胞周期以响应损伤。基因表达的翻译控制已成为卫星细胞活性的重要调节剂。静止的卫星细胞维持低水平的蛋白质合成并选择性地翻译特定的mRNA以保存有限的能量。活化的卫星细胞迅速恢复整体蛋白质合成以满足参与肌肉修复的增殖肌原祖细胞的需求。我们提出了一个模型,通过该模型,翻译控制可以使蛋白质水平快速变化以响应损伤引起的环境变化,既是静止时的制动机制,又是伤害反应的加速器。在这一章中,我们导航处理,新转录mRNA的翻译和代谢。我们回顾了在卫星细胞核中mRNA加工过程中发生的mRNA修饰,并说明这些修饰如何影响mRNA的翻译和稳定性。在细胞质中,我们回顾了通路如何协同工作来调节全球蛋白质合成,而反式作用的microRNA和RNA结合蛋白在严格调节的蛋白质合成的背景下修饰特定的mRNA翻译。在导航卫星细胞中基因表达的翻译控制时,本章揭示了尽管取得了重大进展,该领域在细胞生物学翻译控制的更广泛范围内仍处于起步阶段。我们建议,未来的研究将受益于纳入新兴的全球分析,以研究稀有卫星细胞中基因表达的翻译控制。我们提出了悬而未决的问题,值得未来的探索。
    Satellite cells, named for their satellite position around the sarcolemma of the myofibre, are responsible for skeletal muscle regeneration. Satellite cells normally reside in a quiescent state, but rapidly activate the myogenic program and the cell cycle in response to injury. Translational control of gene expression has emerged as an important regulator of satellite cell activity. Quiescent satellite cells maintain low levels of protein synthesis and selectively translate specific mRNAs to conserve limited energy. Activated satellite cells rapidly restore global protein synthesis to meet the demands of proliferating myogenic progenitors that participate in muscle repair. We propose a model by which translational control enables rapid protein level changes in response to injury-induced environmental shifts, serving as both a brake mechanism during quiescence and an accelerator for injury response. In this Chapter, we navigate the processing, translation and metabolism of newly transcribed mRNAs. We review the modifications of mRNA that occur during mRNA processing in the nucleus of satellite cells, and illustrate how these modifications impact the translation and stability of mRNAs. In the cytoplasm, we review how pathways work in concert to regulate protein synthesis globally, while trans acting microRNAs and RNA binding proteins modify specific mRNA translation within a context of tightly regulated protein synthesis. While navigating translational control of gene expression in satellite cells, this chapter reveals that despite significant progress, the field remains nascent in the broader scope of translational control in cell biology. We propose that future investigations will benefit from incorporating emerging global analyses to study translational control of gene expression in rare satellite cells, and we pose unanswered questions that warrant future exploration.
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