Regulation of Axin2-expressing cells in the adult tendon

很大一部分人口受到肌腱损伤的影响。由于有限 再生潜力，这些损伤是复杂的缓慢和不完善的愈合。为了 开发治疗方法以改善愈合结果，了解其机制是重要的 在动态平衡和愈合过程中调节成人肌腱细胞。肌腱来源的干/祖细胞 细胞已经在体外被鉴定，并显示出干细胞/祖细胞的特征，包括 克隆性、多谱系分化潜能和自我更新。然而，身份和 成体肌腱中常驻祖细胞群体的活动尚不清楚。我们有 鉴定了一种标记为Axin2-Creert2的成体肌腱细胞，该细胞在 体外和体内。肌腱损伤后，Axin2+细胞增殖，渗入损伤部位，并表达 SCX-GFP。此外，我们发现它们的损伤反应依赖于Wnt途径。我们 建议使用谱系追踪、遗传功能丧失和下一代测序 成人肌腱中Axin2+细胞的机制研究 动态平衡和治愈。我们将检验Axin2+细胞是一种独特的肌腱细胞的假设 通过Wnt的分泌和反应，是肌腱愈合的关键协调者的人群。 首先，我们将测试Wnt信号在维持Axin2+祖细胞特性中的作用 动态平衡。接下来，我们将定义Wnt分泌的功能和规范的Wnt信号在 调节肌腱愈合早期和后期的Axin2细胞损伤反应。我们还将测试 如果激活规范的Wnt信号促进Axin2+细胞身份和损伤反应， 从而改善了治疗效果。对Axin2+细胞功能的机械理解是一种 向扩大我们对成人肌腱生物学的基本理解迈出了不可或缺的一步。这 知识可能会影响新疗法的设计，以改善患者的肌腱愈合。

A significant portion of the population is affected by tendon injuries. Due to limited regenerative potential, these injuries are complicated by slow and imperfect healing. In order to develop therapies to improve healing outcomes, it is important to understand the mechanisms regulating adult tendon cells during homeostasis and healing. Tendon-derived stem/progenitor cells have been identified in vitro and display stem/progenitor characteristics, including clonogenicity, multilineage differentiation potential, and self-renewal. However, the identity and activity of resident progenitor populations in the adult tendon are not well understood. We have identified an adult tendon cell marked by Axin2-CreERt2 that displays progenitor-like activities in vitro and in vivo. After tendon injury, Axin2+ cells proliferate, infiltrate the injury site, and express Scx-GFP. In addition, we find their injury response is dependent upon the Wnt pathway. We propose to use lineage tracing, genetic loss of function, and next generation sequencing techniques to gain a mechanistic understanding of Axin2+ cells in the adult tendon during homeostasis and healing. We will test the hypothesis that Axin2+ cells are a unique tendon cell population that, through Wnt secretion and response, are key orchestrators of tendon healing. First, we will test the function of Wnt signaling in maintaining Axin2+ progenitor cell identity during homeostasis. Next, we will define the function of Wnt secretion and canonical Wnt signaling in regulating Axin2 cell injury response at early and later stages of tendon healing. We will also test if activation of canonical Wnt signaling promotes Axin2+ cell identities and injury response, leading to improved healing outcomes. A mechanistic understanding of Axin2+ cell function is an integral step towards expanding our fundamental understanding of adult tendon biology. This knowledge could impact the design of new therapies to improve tendon healing in patients.