Replicative Potential of Muscle Stem Cells

肌肉干细胞的复制潜力

• 批准号: 9403495
• 负责人: Bradley B Olwin
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-28 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403495
• 关键词: Adult; Affect; Aging; Basal lamina; Biological Assay; Cell Count; Cell Surface Proteins; Cell physiology; Cells; Complex; Data; Disease; Elements; Event; Fibroblast Growth Factor Receptor 2; Fibroblast Growth Factor Receptors; Financial compensation; Functional disorder; Generations; Genetic; Goals; Health Care Costs; Hospitalization; Injury; Knock-out; Ligation; Locomotion; Longevity; Mitotic; Modeling; Morbidity - disease rate; Muscle; Muscle function; Muscle satellite cell; Myoblasts; Myopathy; Natural regeneration; Neuromuscular Diseases; Physiological; Population; Proteins; Quality of life; Respiration; Signal Transduction; Skeletal Muscle; Stem cells; Testing; experimental study; genetic analysis; in vivo; live cell imaging; muscle regeneration; patient home care; prevent; protein complex; restoration; satellite cell; self-renewal; skeletal muscle wasting; syndecan-4; therapy development; wasting

Summary Skeletal muscle tissue is maintained and can be dynamically modeled to fit ongoing needs by changes in muscular activity. Myofibers, the primary cells that comprise the contractile elements of skeletal muscle, are post-mitotic and maintained by a pool of stem cells, termed satellite cells, which are localized to a niche between the myofiber and overlying basal lamina. Loss of mobility arising from loss of skeletal muscle function occurs following an injury, is an inevitable consequence of aging and a consequence of many neuromuscular diseases, the latter two resulting in reduced quality of life and increased morbidity, requiring hospitalization or home care, significantly raising health care costs. These complex physiological changes are well documented but the mechanisms responsible for these changes are not understood. Satellite cells can (i) renew their own population, (ii) commit to the myoblast lineage and pro- liferate as myoblasts, and (iii) undergo terminal differentiation and fuse into existing myofibers or fuse to form new myofibers as myonuclei. Satellite cell turnover is extensive in adult muscle yet rela- tively constant numbers of satellite cells are maintained. Following an induced injury satellite cell numbers return to their pre-injury numbers, suggesting remarkably stringent control of satellite cell numbers. These observations prompt one to ask how satellite cell numbers are maintained and what is the function of satellite cell turnover? Timed EdU administration following an induced muscle injury revealed that SCs are generated only upon completion of myonuclear expansion at ~4-5d post-injury in vivo. Thus, the rapid expan- sion of myoblasts occurring upon muscle injury is exclusively devoted to cells that undergo terminal differentiation to produce myonuclei. What mechanisms prevent self-renewal early during regenera- tion and then promote self-renewal once sufficient myonuclei are generated? As SCs most likely arise by asymmetric division, a major goal of our proposed experiments in this application are aimed to gain a better understand the mechanisms governing SC self-renewal during skeletal muscle regenera- tion. We propose that asymmetric division is required for satellite cell restoration during muscle re- generation. Signaling from ectopically activated FGF Receptor 1 simultaneously represses terminal differentiation, induces asymmetry and promotes asymmetric division. We plan to test this idea by initially characterizing satellite cell self-renewal during muscle regeneration, and then identifying ge- netic interactions required for satellite cell self-renewal and then to identify genetic interactions re- quired for satellite cell self-renewal.

总结 骨骼肌组织被维持，并且可以动态地建模以适应持续的需求， 肌肉活动的变化。肌纤维是构成肌纤维收缩成分的初级细胞， 骨骼肌是有丝分裂后的，由称为卫星细胞的干细胞库维持， 定位于肌纤维和上覆基底层之间的小生境。丧失流动性 骨骼肌功能的丧失发生在受伤之后，是衰老的必然结果。 以及许多神经肌肉疾病的后果，后两种疾病导致生活质量下降 发病率增加，需要住院治疗或家庭护理， 成本这些复杂的生理变化是有据可查的，但机制负责 这些变化不被理解。 卫星细胞可以（i）更新自己的种群，（ii）致力于成肌细胞谱系， 生成成肌细胞，和（iii）经历终末分化并融合成现有的肌纤维，或 融合形成新的肌纤维作为肌核。卫星细胞周转在成人肌肉中是广泛的， 维持卫星小区的数量恒定。在诱导损伤卫星细胞后， 数量恢复到损伤前的数量，这表明对卫星细胞的控制非常严格。 号码这些观察促使人们问卫星细胞的数量是如何维持的， 是卫星细胞更替的功能吗 在诱导的肌肉损伤后定时给予EdU显示， 仅在体内损伤后约4-5d完成肌层扩张时。而快速的扩张， 在肌肉损伤时发生的成肌细胞的锡永专门用于经历终末损伤的细胞。 分化以产生肌核。在再生过程中，什么机制阻止了早期的自我更新？ 一旦产生足够的肌核，就促进自我更新？由于SC最有可能出现， 通过不对称分割，我们在该应用中提出的实验的主要目标旨在 更好地了解骨骼肌再生过程中SC自我更新的机制- 是的。 我们认为，肌肉再生过程中卫星细胞的恢复需要不对称分裂。 一代异位激活FGF受体1的信号传导同时抑制终末 分化，诱导不对称，促进不对称分裂。我们计划测试这个想法， 首先表征肌肉再生过程中卫星细胞的自我更新，然后鉴定ge- 卫星细胞自我更新所需的遗传相互作用，然后确定遗传相互作用， 用于卫星小区自我更新。