Cadherin-Dependent Regulation of Satellite Cell Function

卫星细胞功能的钙粘蛋白依赖性调节

• 批准号: 9160344
• 负责人: Robert S. Krauss
• 金额: $ 41.03万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9160344
• 关键词: Address; Adhesions; Adhesives; Adult; Applications Grants; Basal lamina; Behavior; Biological Models; Biology; Cadherins; Cell Adhesion; Cell Adhesion Molecules; Cell Count; Cell Therapy; Cell model; Cell physiology; Cell-Cell Adhesion; Cells; Cellular biology; Environment; Excision; Functional disorder; Gene Expression; Genes; Genetic; Homeostasis; In Vitro; Injury; Ligation; M-cadherin; Maintenance; Mediating; Molecular; Mus; Muscle; Muscle function; Muscle satellite cell; Muscular Dystrophies; Myoblasts; Myopathy; N-Cadherin; Natural regeneration; Nature; Nuclear Translocation; Pathway interactions; Phenotype; Process; Property; Proteins; Regulation; Research; Role; Signal Transduction; Skeletal Muscle; Stem cells; Structure; Testing; Therapeutic; Work; adult stem cell; age-related muscle loss; alpha catenin; base; beta catenin; cell behavior; in vivo; insight; mdx mouse; muscle aging; regenerative; repaired; research study; satellite cell; self-renewal; stem cell niche; stem cell population

SUMMARY Skeletal muscle has remarkable capacity for regeneration following injury. This capability derives from resident muscle stem cells, known as satellite cells (SCs), which reside between the myofiber and its surrounding basal lamina. During normal homeostatic maintenance of adult muscle, SCs are quiescent. Following injury, they are “activated” to generate the myoblasts required for regeneration and self-renew to replenish the SC pool. Stem cells, including SCs, reside in a specialized microenvironment, or “niche”, that supports their behavior, as demand requires. Niche-dependent maintenance of SC quiescence is of particular importance as breaking quiescence in SCs generally leads to depletion of the SC pool and impaired regenerative capability. SCs may be useful in cell-based therapies for muscular dystrophies and myopathies, or for age-related muscle loss. Alternatively, it has been proposed that targeting stem cell niches themselves may enhance the therapeutic potential of endogenous stem cell populations. Therefore, a thorough understanding of the SC niche is both fundamental to muscle biology and critical for harnessing SCs for therapeutic purposes. A major constituent of the quiescence-inducing SC niche is the myofiber itself, but little is known of the molecular components that mediate this phenomenon. We have now identified the cell-cell adhesion molecules N-cadherin (Ncad) and M- cadherin (Mcad) as quiescence-promoting factors of the SC niche. SCs in mice lacking Ncad/Mcad (dKO mice) break quiescence in vivo, but unlike most other instances in which SC quiescence is broken, loss of these cadherins results in a stable increase in SC numbers that persists for at least one year. Furthermore, dKO mice repair both single and triple injuries similarly to control mice. Strikingly, dKO mice replenish their SC numbers to the same elevated level they had prior to injury, even after the triple injury. Loss of SC quiescence in dKO mice is therefore associated with an apparently stable expansion of the SC pool. dKO SCs may be in a partial state of activation; this is associated with an incomplete perturbation of cadherin-based adhesive structures that includes nuclear translocation of a fraction of SC β-catenin. Our findings raise important questions about the nature of the adhesive niche itself and how it promotes SC quiescence. To gain further insight into these processes, the following aims are proposed: 1. Determine the nature of the cadherin-based adhesive SC niche and the consequences of cadherin loss in SCs on mdx mice; and 2. Determine the roles of the catenin proteins as niche factors in SC adhesion, quiescence, and activation. SCs have potential therapeutic value and have served as an enormously valuable stem cell model system. Cell-autonomous properties of SCs are much better understood than is niche-dependent regulation of SC behavior. The experiments proposed in this grant application seek to address this gap with reference to cadherins as SC niche factors. Successful completion of the proposed aims will provide highly significant information for muscle and SC biology generally and in relation to the ability to exploit SCs in a therapeutic context.

总结 骨骼肌在损伤后具有显著的再生能力。这种能力来源于居民 肌肉干细胞，称为卫星细胞（SC），位于肌纤维及其周围基底层之间， 层。在成年肌肉的正常稳态维持期间，SC是静止的。受伤后，他们 “激活”以产生再生和自我更新所需的成肌细胞以补充SC池。干 细胞，包括SC，居住在一个专门的微环境，或“生态位”，支持他们的行为， 需求要求。小生境依赖的SC静止的维持是特别重要的， SC中的静止通常导致SC库的耗尽和再生能力受损。SCs可以 可用于肌营养不良和肌病或与年龄相关的肌肉损失的基于细胞的治疗。 或者，已经提出靶向干细胞小生境本身可以增强治疗效果。 内源性干细胞群体的潜力。因此，对供应链利基的透彻理解 这是肌肉生物学的基础，对于利用SC用于治疗目的至关重要。的主要成分 诱导静止的SC龛是肌纤维本身，但对 这一现象。我们现在已经确定了细胞间粘附分子N-钙粘蛋白（Ncad）和M- 钙粘蛋白（Mcad）作为SC生态位的静止促进因子。缺乏Ncad/Mcad的小鼠（dKO小鼠）中的SC 打破体内静止，但与大多数其他SC静止被打破的情况不同，这些 钙粘蛋白导致SC数量的稳定增加，持续至少一年。此外，dKO 小鼠与对照小鼠类似地修复单损伤和三损伤。引人注目的是，dKO小鼠补充了它们的SC 数字上升到相同的水平，他们受伤前，即使在三重伤害。SC静止丢失 因此，在dKO小鼠中，与SC库的明显稳定扩增相关。dKO SC可以处于 部分激活状态;这与钙粘蛋白基粘合剂的不完全扰动有关 包括SC β-连环蛋白部分核转位的结构。我们的发现对 问题的性质的粘合剂利基本身，以及它如何促进SC静止。为了获得进一步 深入了解这些过程，提出了以下目标：1。确定基于钙粘蛋白的 粘附SC生态位和mdx小鼠SC中钙粘蛋白损失的后果;和2.确定的角色 catenin蛋白在SC粘附、静止和活化中作为生态位因子。SC具有潜力 治疗价值，并作为一个非常有价值的干细胞模型系统。细胞自主 SC的特性比SC行为的生态位依赖性调节更容易理解。的 在这项拨款申请中提出的实验试图解决这个空白，参考钙粘蛋白作为SC 生态位因素成功完成所提出的目标将提供非常重要的信息，肌肉 和SC生物学以及在治疗背景下利用SC的能力。