Regulation of Muscle Stem Cell Number via Paracrine Signaling

摘要： 成年骨骼肌在运动、创伤或疾病引起的损伤后具有修复和再生的能力。 尽管由核不能分裂的多核肌纤维组成，但仍有损伤。此属性是 主要归因于成体肌原性前体细胞（卫星细胞）。当响应本地 肌肉损伤，卫星细胞广泛增殖，自我更新，以重建储备肌肉 祖细胞池或分化成新的骨骼肌纤维通过相互融合或融入现有的 肌肉纤维由于卫星细胞显示谱系特异性分化（肌细胞）和自我更新， 由于干细胞的特性，它们被认为是骨骼肌的主要驻留成体干细胞。而 自从1961年发现卫星细胞生物学以来，密集的研究努力已经推进了我们对卫星细胞生物学的理解， 控制卫星小区数量的调节机制仍然未知。在这里我们提供证据 涉及FGF 6信号传导，其可由骨骼肌中的Hippo通路介导剂TEAD 1调节 纤维，在成年小鼠卫星细胞数量的调节。我们以前研究了一种小鼠模型， 转基因TEAD 1在肌纤维中的过度表达，并发现在肌纤维中显著增加高达6倍。 卫星细胞的数量没有任何变化的整体肌肉大小。我们进一步确定旁分泌 来自该小鼠模型中卫星细胞库扩增的TEAD 1表达肌纤维信号的信号。 将转录组学应用于该小鼠模型，我们已经鉴定了FGF信号传导，即FGF 2和FGF 6， 调节卫星细胞池大小的生理相关途径。事实上，我们对骨骼的初步分析 来自Fgf 6突变小鼠的肌肉揭示了卫星细胞数量的显著减少。这种减少是 在小鼠中进一步恶化，其中主要由卫星细胞表达的两种FGF受体被 在生肌谱系中特异性失活。我们的目标是确定FGF信号转导的作用， 肌纤维的卫星细胞在实现特定池大小的成人肌肉祖细胞的有效修复 以及肌纤维特异性TEAD 1如何调节来自肌肉组织的旁分泌信号。 肌纤维有助于调节这一过程。具体目的：1）确定FGF 6和FGF 2在以下中的作用： 2）确定Fgfr 1和Fgfr 4在围产期SC中的作用， 在成年期，3）确定肌纤维内TEAD介导的转录调节如何调控SC 池缩放。我们期待着新的基本发现，肌肉中卫星细胞群的大小是如何变化的。 在发育过程中指定，并在成年生活中适应性地维持。深入了解 肌肉中的再生细胞（干细胞）是受控的， 用于治疗肌肉萎缩疾病、运动/战斗损伤和年龄相关的肌肉减少症。

ABSTRACT: Adult skeletal muscle has the ability to repair and regenerate following exercise, trauma or disease-induced damage despite being comprised of multinucleated muscle fibers whose nuclei cannot divide. This property is primarily attributable to adult myogenic precursor cells (satellite cells). When activated in response to local muscle damage, satellite cells proliferate extensively, either self-renew to reconstitute the reserve muscle progenitor pool or differentiate into new skeletal muscle fibers by fusing with each other or into the existing muscle fiber. Because satellite cells display lineage-specific differentiation (muscle cell) and self-renewal, two characteristics of stem cells, they are considered the primary resident adult stem cells of skeletal muscle. While intensive research efforts have advanced our understanding of satellite cell biology since their discovery in 1961, the regulatory mechanism(s) controlling satellite cell number remain unknown. Here we provide evidence implicating FGF6 signaling, which can be modulated by the Hippo pathway mediator TEAD1 in skeletal muscle fibers, in the regulation of adult mouse satellite cell number. We previously investigated a mouse model with transgenic TEAD1 overexpression in the muscle fiber and discovered a remarkable up to 6-fold increase in the number of satellite cells without any changes in overall muscle size. We further determined that paracrine signal(s) from the TEAD1-expressing myofiber signal for the satellite cell pool expansion in this mouse model. Applying transcriptomics to this mouse model, we have identified FGF signaling, i.e. FGF2 and FGF6, as a physiologically relevant pathway regulating satellite cell pool size. Indeed, our preliminary analysis of skeletal muscle from Fgf6 mutant mice reveals a significant reduction in the number of satellite cells. This reduction is further exacerbated in mice, in which the two FGF receptors predominantly expressed by satellite cells are inactivated specifically in the myogenic lineage. Our goal is to determine the role of FGF signaling from the myofiber to the satellite cell in achieving a particular pool size of adult muscle progenitor cells for effective repair of muscle tissue throughout life, and how myofiber-specific TEAD1 is regulating paracrine signaling from the myofiber to contribute to regulate this process. Specific Aims: 1) Determine the role of FGF6 and FGF2 in perinatal SC scaling and adult muscle regeneration, 2) Determine the role of Fgfr1 and Fgfr4 in the SC perinatally and in adulthood, 3) Determine how TEAD-mediated transcriptional regulation within the myofiber governs SC pool scaling. We expect new fundamental findings into how the size of the satellite cell population in muscle is specified during development and adaptively maintained during adult life. Insight into how the number of regenerative cells (stem cells) in muscle is controlled provides an entry into the development of new cell-based therapies against muscle wasting diseases, sport/combat injury, and age-related sarcopenia.