Regulation of Muscle Stem Cell Number via Paracrine Signaling

摘要： 成人骨骼肌在运动、创伤或疾病后具有修复和再生的能力 尽管由多核肌肉纤维组成，但其核不能分裂，但仍会造成损害。此属性是 主要归因于成人成肌前体细胞(卫星细胞)。在响应本地时激活 肌肉受损，卫星细胞广泛增殖，要么自我更新，重建储备肌肉 祖细胞通过彼此融合或分化为新的骨骼肌纤维或分化为现有的 肌肉纤维。由于卫星细胞表现出谱系特异性分化(肌肉细胞)和自我更新，两个 干细胞的特性，它们被认为是骨骼肌的主要成体干细胞。而当 自从1961年发现卫星细胞以来，密集的研究工作促进了我们对卫星细胞生物学的理解， 控制卫星细胞数量的调控机制(S)尚不清楚。在这里，我们提供了证据 骨骼肌中HIPPO通路介导物TEAD1可调节FGF6信号转导 纤维，在成年小鼠卫星细胞数量的调节中。我们之前研究了一种小鼠模型 转基因TEAD1在肌肉纤维中过表达，发现在 在总体肌肉大小没有任何变化的情况下，卫星细胞的数量。我们进一步确定旁分泌 在这个小鼠模型中，来自TEAD1的信号(S)表达了卫星细胞池扩大的肌纤维信号。 在这个小鼠模型中，我们应用转录转录技术，已经鉴定出成纤维细胞生长因子信号，即FGF2和FGF6，是一种 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Fgf6突变小鼠的肌肉显示卫星细胞的数量显著减少。这一减幅是 在小鼠中进一步加剧，其中两个主要由卫星细胞表达的成纤维细胞生长因子受体是 在肌源性谱系中是特定失活的。我们的目标是确定成纤维细胞生长因子信号的作用 肌纤维到卫星细胞中达到特定大小的成体肌祖细胞进行有效修复 以及肌纤维特异的TEAD1是如何调节来自 肌纤维有助于调节这一过程。具体目标：1)确定FGF6和FGF2在 围产期SC伸缩与成人肌肉再生2)FGFR1和FGFR4在围产期SC中的作用 在成年期，3)确定Tead介导的肌纤维内转录调控如何调控SC 池扩展。我们期待着关于肌肉中卫星细胞数量大小的新的基本发现 在发育过程中指定，并在成年后适应性地保持。洞察数字是如何 再生细胞(干细胞)在肌肉中的调控为进入新的细胞基础的发展提供了条件 治疗肌肉萎缩疾病、运动/战斗损伤和与年龄相关的石棺减少症。

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.