Regulation of Axin2-expressing cells in the adult tendon

成人肌腱中 Axin2 表达细胞的调节

• 批准号: 10442925
• 负责人: JENNA L GALLOWAY
• 金额: $ 49.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442925
• 关键词: Adult; Affect; Behavior; Biological Assay; Biology; Birth; Cell Culture Techniques; Cell Differentiation process; Cell physiology; Cell surface; Cells; Characteristics; Clinical; Data; Defect; Development; Disease; Excision; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Homeostasis; Human; Impaired healing; In Vitro; Individual; Infiltration; Injury; Knowledge; Label; Maintenance; Mediating; Modeling; Molecular; Movement; Mus; Neonatal; Outcome; Pathway interactions; Patients; Population; Porcupines; Production; Proliferating; Proteins; Regenerative Medicine; Regenerative capacity; Regulation; Role; Signal Transduction; Site; Techniques; Tendon Injuries; Tendon structure; Testing; Therapeutic; WNT Signaling Pathway; achilles tendon; beta catenin; cell injury; cell type; design; fetal; healing; improved; in vitro activity; in vivo; loss of function; mouse genetics; next generation sequencing; novel strategies; novel therapeutics; patellar tendon; progenitor; programs; recruit; regeneration potential; regenerative; repaired; response; response to injury; self-renewal; stem; stem cells; therapy development

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.

很大一部分人口受到肌腱损伤的影响。由于有限的 再生潜力，这些伤害是复杂的缓慢和不完善的愈合。为了 开发治疗方法以改善治疗效果，了解其机制非常重要 在体内平衡和愈合过程中调节成年肌腱细胞。腱源性干/祖细胞 细胞已经在体外被鉴定并显示干/祖细胞特征，包括 克隆形成、多系分化潜能和自我更新。然而，身份和 成年肌腱中的常驻祖细胞群的活性还不太清楚。我们有 鉴定了一种由Axin2-CreERt2标记的成年肌腱细胞，该细胞在 体外和体内。肌腱损伤后，Axin2+细胞增殖，浸润损伤部位，并表达Axin2+。 Scx-GFP。此外，我们发现它们的损伤反应依赖于Wnt通路。我们 建议使用谱系追踪、遗传功能丧失和下一代测序 技术，以获得对成年肌腱中Axin2+细胞的机械理解， 体内平衡和愈合。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。 首先，我们将测试Wnt信号传导在维持Axin2+祖细胞身份中的功能。 体内平衡接下来，我们将定义Wnt分泌和经典Wnt信号转导在细胞中的功能。 在肌腱愈合的早期和后期调节Axin2细胞损伤反应。我们还将测试 如果经典Wnt信号传导的激活促进Axin2+细胞特性和损伤应答， 从而改善愈合效果。对Axin2+细胞功能的机制理解是一个重要的研究方向。 这是我们对成人肌腱生物学基本理解的重要一步。这 这些知识可能会影响新疗法的设计，以改善患者的肌腱愈合。