Myogenic stem cells in extraocular muscles

眼外肌中的肌源干细胞

• 批准号: 8305524
• 负责人: ZIPORA YABLONKA-REUVENI
• 金额: $ 30.43万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305524
• 关键词: Address; Adult; Age; Aging; Animal Model; Antigens; Atrophic; Basal lamina; Cell Culture Techniques; Cell Nucleus; Cell Separation; Cells; Characteristics; Complex; Data; Deterioration; Development; Disease; Duchenne muscular dystrophy; Dystrophin; Endothelial Cells; Endothelium; Exhibits; Eye Movements; Genes; Glycoproteins; Goals; Growth; Harvest; Head; Hindlimb; Impairment; Knockout Mice; Life; Light; Limb structure; Link; Location; Maintenance; Mesoderm; Modeling; Molecular; Monitor; Mus; Muscle; Muscle Fibers; Muscle rehabilitation; Muscle satellite cell; Muscular Atrophy; Muscular Dystrophies; Myopathy; Performance; Pericytes; Pilot Projects; Play; Population; Preparation; Process; Proliferating; Property; Regulatory Element; Reporter Genes; Reporting; Reserve Cell; Respiratory Diaphragm; Role; Skeletal Muscle; Skeletal Muscle Satellite Cells; Sorting - Cell Movement; Source; Stem cells; Supporting Cell; Transgenic Organisms; base; cell type; functional status; in vivo; insight; interstitial; myogenesis; nestin protein; orbit muscle; progenitor; rehabilitation strategy; repaired; sarcopenia; satellite cell; skeletal; stem; trait

PROJECT SUMMARY Extraocular muscles (EOMs) are a group of highly specialized skeletal muscles that control eye movements. They develop from the head mesoderm and are molecularly, anatomically and physiologically distinct from other skeletal muscles. EOMs possess a unique quality of being spared in muscular dystrophies associated with impairments in the dystrophin-glycoprotein complex. In Duchenne muscular dystrophy and in animal models of this devastating dystrophin deficiency-associated disease, EOMs are spared, contrary to the severe early- or late-onset damage to other muscles. Specific traits of myogenic progenitors in EOMs may play a role in the preferential sparing of these muscles. Surprisingly, very little is known about the myogenic stem and progenitor cells in adult EOMs. The difficulty in isolating EOMs for harvesting primary cells has resulted in the lack of appropriate cell culture models aimed at identifying the properties of cells that support EOM myofiber maintenance through life. This application proposes to decipher cellular and molecular characteristics of three cell types that display robust growth and renewal properties in EOMs compared to limb and diaphragm muscles, a distinction that may contribute to the sparing of EOMs from dystrophinopathy and age-linked atrophy. These cell types are: a) satellite cells, which are classically recognized as the main source of myogenic progenitors in adult skeletal muscle; b) interstitial myogenic progenitors; c) microvascular-associated contractile cells (i.e., pericytes), which may fuse directly with myofibers. The proposed studies aim to: 1) characterize myogenic-specific marker expression by cells in the satellite cell and interstitium niches of EOMs versus limb and diaphragm muscles; 2) compare growth and renewal potential of myogenic stem and progenitor cells in EOMs versus limb and diaphragm muscles; 3) investigate the potential of donor satellite cells and pericytes from EOMs versus limb and diaphragm muscles to contribute to in vivo muscle repair. Cells from wildtype and dystrophin-null mice that carry various reporter genes (for tracing the different cell types and their progeny) will be investigated in vivo and in culture. The expected results of the proposed studies will contribute to a better understanding of the cellular milieu that supports EOM maintenance in adult life and will provide new insights regarding the role of microvasculature-associated cells in skeletal myogenesis. Further characterization of EOM myogenic progenitors is essential for developing repair strategies to treat extraocular muscle disorders. The proposed studies will also shed new light on the functional status of myogenic progenitors in aging and dystrophin-deficient muscles, providing important information for muscle rehabilitation strategies.

项目概要 眼外肌 (EOM) 是一组高度专业化的骨骼肌，控制眼睛 动作。它们从头部中胚层发育而来，在分子、解剖学和 生理上与其他骨骼肌不同。 EOM 具有独特的品质，能够幸免于难 与肌营养不良蛋白-糖蛋白复合物损伤相关的肌营养不良症。在杜兴 肌营养不良症和这种破坏性肌营养不良蛋白缺乏相关疾病的动物模型， EOM 幸免于难，与其他肌肉严重的早发型或晚发型损伤相反。具体特征 EOM 中的肌源性祖细胞可能在优先保护这些肌肉中发挥作用。出奇， 对于成体 EOM 中的肌源性干细胞和祖细胞知之甚少。困难在于 分离 EOM 来收获原代细胞导致缺乏合适的细胞培养模型 旨在确定支持 EOM 肌纤维终生维持的细胞特性。 该应用旨在破译三种细胞类型的细胞和分子特征 与肢体和膈肌相比，EOM 表现出强劲的生长和更新特性， 这种区别可能有助于 EOM 免受肌营养不良症和年龄相关性萎缩的影响。 这些细胞类型是： a) 卫星细胞，通常被认为是肌源性的主要来源 成人骨骼肌的祖细胞； b) 间质肌源性祖细胞； c) 微血管相关 收缩细胞（即周细胞），可以直接与肌纤维融合。拟议的研究旨在：1) 表征卫星细胞和间质壁龛中细胞的肌源性特异性标记物表达 EOM 与肢体和膈肌； 2）比较生肌茎的生长和更新潜力 以及 EOM 中的祖细胞与肢体和膈肌的比较； 3）调查捐赠者的潜力 来自 EOM 的卫星细胞和周细胞与肢体和膈肌在体内的贡献 肌肉修复。来自携带各种报告基因（用于追踪 不同的细胞类型及其后代）将在体内和培养中进行研究。预期结果 拟议的研究将有助于更好地理解支持 EOM 的细胞环境 成人生活中的维持，并将提供有关微血管相关的作用的新见解 骨骼肌生成中的细胞。 EOM 肌源性祖细胞的进一步表征对于 制定治疗眼外肌疾病的修复策略。拟议的研究还将揭示 关于衰老和肌营养不良蛋白缺陷肌肉中肌原祖细胞功能状态的新认识， 为肌肉康复策略提供重要信息。