Role of extracellular matrix in age-related declines of muscle regeneration

细胞外基质在年龄相关的肌肉再生衰退中的作用

• 批准号: 10399525
• 负责人: Fabrisia Ambrosio
• 金额: $ 43.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-09-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399525
• 关键词: 3-Dimensional; Achievement; Address; Affect; Age; Aging; Animals; Architecture; Biochemical; Bioenergetics; Biological Models; Biomechanics; Biophysics; Cell Lineage; Cell physiology; Cells; Characteristics; Collagen; Collagen Fibril; Cues; Custom; Deposition; Deterioration; Development; Elasticity; Elderly; Engineering; Epigenetic Process; Exposure to; Extracellular Matrix; Fibroblasts; Fibrosis; Foundations; Functional disorder; Gene Expression; Goals; Image; Impaired healing; Impairment; In Vitro; Individual; Injury; Instruction; Knowledge; Laboratories; Longevity; Measures; Mechanical Stimulation; Mechanics; Mediating; Methods; Methylation; Modification; Modulus; Molecular; Morphology; Muscle; Muscle satellite cell; Natural regeneration; Operative Surgical Procedures; Pathogenicity; Play; Population; Property; Proteins; Recovery of Function; Regenerative capacity; Regenerative response; Repression; Reserve Cell; Resolution; Role; Signal Transduction; Skeletal Muscle; Skeletal muscle injury; Stretching; System; Testing; Time; Tissue Engineering; Tissues; Trauma; age effect; age related; age-related muscle loss; aged; biophysical properties; cell behavior; design; functional decline; healing; histone modification; impaired driving performance; improved; in vitro Model; in vivo; injury recovery; insight; interest; mechanical load; mechanical stimulus; mouse model; muscle aging; muscle regeneration; neuromuscular stimulation; novel; novel therapeutics; osteogenic; pressure; promoter; regeneration potential; response; satellite cell; self-renewal; stem; stem cell biology; stem cell function; stem cell niche; stem cells; tissue regeneration

ABSTRACT Skeletal muscle trauma resulting from an injury or surgery often results in significant functional declines in older adults. These declines are at least partially attributed to failed muscle healing. Muscle regeneration is predominantly dictated by the action of muscle stem, or “satellite”, cells (MuSCs), a reserve cell population that typically demonstrates considerable dysfunction with increasing age. According to the stem cell “niche” concept, stem cell responses are largely determined by biophysical and biochemical cues that emanate from the surrounding microenvironment. Indeed, expanding recognition of the influence of the microenvironment on stem cell behavior has led to a recent surge in the development of bioinspired and engineered extracellular matrix (ECM) approaches for the treatment of skeletal muscle injuries. Still lacking, however, is an in-depth knowledge of whether and how pathogenic instructional characteristics of the native ECM disrupt MuSC function and skeletal muscle regeneration. While it is evident that MuSC activation, self-renewal, proliferation and differentiation are influenced by physical and dynamic niche interactions, a mechanistic understanding of the direct impact of age-related ECM alterations on skeletal muscle regenerative capacity is unknown. The over-arching goal of this project is to test our central hypothesis that age-related biophysical alterations in the skeletal muscle ECM promotes a fibrogenic conversion in MuSCs, ultimately driving impaired skeletal muscle regeneration. Further, we hypothesize that these pathogenic biophysical changes may be reverted, at least partially, by mechanical stimulation. To achieve this goal, we will employ an integrated approach that encompasses cutting-edge super-resolution imaging and 3-D tissue engineering methods to address two specific aims. Aim 1 studies will measure, manipulate, and mimic the biophysical properties of young and aged skeletal muscle ECM in order to dissect the effect of age-related architectural and elastic ECM modifications on MuSC fate. Aim 2 studies will identify mechanisms by which mechanical stimulation modulates biophysical properties of the aged ECM to promote MuSC myogenicity and muscle regeneration. Successful achievement of these aims will further our understanding of 1) the instructional capabilities of the native ECM on MuSC lineage specification, 2) how these instructional capabilities change over time, and 3) the molecular mechanisms controlling age-related declines in skeletal muscle regenerative potential. Taken together, successful completion of these studies may provide a foundation for the identification of novel ECM targets in the treatment of skeletal muscle injuries for a geriatric population. More broadly, an improved insight into how age-associated alterations in biomechanical, architectural and dynamic ECM properties direct MuSC function will expand our fundamental understanding of aging and stem cell biology.

抽象的 受伤或手术造成的骨骼肌创伤通常会导致显着的功能下降 在老年人中。这些下降至少部分归因于肌肉愈合失败。肌肉再生是 主要由肌肉干细胞或“卫星”细胞 (MuSC) 的作用决定，肌肉干细胞是一种储备细胞群， 随着年龄的增长，通常表现出相当大的功能障碍。根据干细胞“生态位” 从概念上讲，干细胞反应很大程度上取决于来自以下部位的生物物理和生化线索： 周围的微环境。事实上，人们越来越认识到微环境对 干细胞行为导致最近生物启发和工程化细胞外细胞的发展激增 用于治疗骨骼肌损伤的矩阵（ECM）方法。但仍缺乏深入的 了解天然 ECM 的致病性特征是否以及如何破坏 MuSC 功能和骨骼肌再生。虽然很明显 MuSC 激活、自我更新、增殖 和分化受到物理和动态生态位相互作用的影响，这是对 与年龄相关的 ECM 改变对骨骼肌再生能力的直接影响尚不清楚。 该项目的首要目标是检验我们的中心假设，即与年龄相关的生物物理 骨骼肌 ECM 的改变促进 MuSC 的纤维化转化，最终驱动 骨骼肌再生受损。此外，我们假设这些致病性生物物理 机械刺激可以至少部分地恢复变化。为了实现这一目标，我们将 采用包含尖端超分辨率成像和 3D 组织的集成方法 解决两个特定目标的工程方法。目标 1 研究将测量、操纵和模仿 年轻和老年骨骼肌 ECM 的生物物理特性，以剖析年龄相关的影响 MuSC 命运的结构和弹性 ECM 修改。目标 2 研究将确定机制 机械刺激调节老化 ECM 的生物物理特性，以促进 MuSC 生肌性和 肌肉再生。成功实现这些目标将进一步加深我们对以下方面的理解：1) MuSC 谱系规范上的原生 ECM 的教学能力，2) 这些教学如何 能力随着时间的推移而变化，3）控制与年龄相关的骨骼衰退的分子机制 肌肉再生潜力。总而言之，成功完成这些研究可能会提供 为识别治疗老年骨骼肌损伤的新型 ECM 靶点奠定基础 人口。更广泛地说，更好地了解与年龄相关的生物力学变化， 架构和动态 ECM 属性直接 MuSC 功能将扩展我们对 衰老和干细胞生物学。