The role of TSCs in the degenerative tendinopathy induced by mechanical loading

 描述(申请人提供)：退行性肌腱病的特征是在肌腱基质中形成非肌腱组织。这种肌腱疾病是导致慢性残疾的主要原因，影响着数百万美国人。在过去的几十年里，人们进行了大量的研究，但退行性肌腱病的发病机制仍不清楚，因此，目前对该疾病的治疗大多是姑息性的。最近，我们等人发现肌腱/祖细胞干细胞(TSCs)具有多向分化潜能，在体内外均可分化为脂肪细胞、软骨细胞和骨细胞。TSCs形成的多种细胞类型与人类肌腱病肌腱中观察到的三种非腱组织相对应：脂肪组织、软骨样组织和骨组织。此外，我们发现过高的机械负荷本身就足以诱导TSCs分化为非腱细胞系。根据这些令人兴奋的发现，我们假设TSCs是退行性肌腱病的主要贡献者，退行性肌腱病是由于它们在肌腱上施加过多的机械负荷而异常分化为非腱细胞系的结果。为了验证这一创新假说，我们在该项目中提出了两个主要目标：(1)通过使用一种新的体外模型系统来分析细胞的增殖、自我更新和分化，来确定机械负荷对TSCs的影响；(2)通过建立小鼠跑步机跑步模型，在体内确定过高的机械负荷条件对小鼠肌腱的影响。第二个目标包括两个子目标，即确定“过度使用”和“过度负荷”对小鼠肌腱的影响。我们提出的研究的关键创新之处在于，他们将通过阐明和分析TSCs在细胞、组织和功能水平上的作用来揭示肌腱的机械生物学反应，这些因素与重要的疾病过程直接相关。这项研究是确定TSCs在退行性肌腱病发病中的致病作用的初步努力。这项研究的成功完成将揭示退行性肌腱病基于干细胞的机制。这将导致新的预防和治疗策略，如通过阻止TSCs分化为非腱细胞来靶向TSCs，以及改变运动员和门外汉的训练方案，这将比目前主要依赖抗炎药物的肌腱病治疗方法更有效。

 DESCRIPTION (provided by applicant): Degenerative tendinopathy is characterized by the formation of non-tendinous tissues in the tendon matrix. This tendon disease is a leading cause of chronic disability and affects millions of Americans. Intensive research has been conducted in the past decades, but the pathogenesis of degenerative tendinopathy remains unclear and, as a result, current treatments of the tendon disease are largely palliative. Recently, we and others identified tendon/progenitor stem cells (TSCs), which exhibit multi-differentiation potential and can differentiate into adipocytes, chondrocytes, and osteocytes both in vitro and in vivo. The diverse cell types formed by TSCs correspond well with three non-tendinous tissues observed in human tendinopathic tendons: fatty tissue, cartilage-like tissue, and bony tissue. Moreover, we discovered that excessive mechanical loading alone is sufficient to induce differentiation of TSCs into non-tenocyte lineages. In light of these exciting findings, we hypothesize that TSCs are the primary contributors to the development of degenerative tendinopathy, which is a result of their aberrant differentiation into non-tenocyte lineages of cells in response to excessive mechanical loading placed on tendons. To test this innovative hypothesis, we propose two major aims in this project: (1) To define the effect of mechanical loading on TSCs by using a novel in vitro model system to analyze cell proliferation, self-renewal, and differentiation; and () to determine the effects of excessive mechanical loading conditions on mouse tendons in vivo using a well-established mouse treadmill running model. The second aim includes two sub-aims, which are to determine the effects of both "over-use" and "over-loading" on mouse tendons. The key innovation of our proposed studies is that they will uncover the mechanobiological responses of tendons by clarifying and analyzing the role of TSCs at the cellular, tissue, and functional levels under well-controlled mechanical loading conditions, which are of direct relevance to an important disease process. This study represents the initial efforts to determine the pathogenic role of TSCs in the development of degenerative tendinopathy. The successful completion of this study will reveal the stem-cell based mechanism of degenerative tendinopathy. This will lead to new prevention and treatment strategies such as targeting TSCs by blocking their differentiation into non-tenocytes and altering training regimens for athletes and laymen alike that will be more effective than current tendinopathy treatment methods, which mostly rely on the use of anti- inflammatory drugs.