Stimulation of tendon repair by retinoid nuclear receptor agonists

类维生素A核受体激动剂刺激肌腱修复

• 批准号: 8700319
• 负责人: MOTOMI ENOMOTO-IWAMOTO
• 金额: $ 18.65万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-12 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700319
• 关键词: Acute; Affect; Agonist; Biochemical; Biological; Biological Assay; Blood Circulation; Cartilage; Cell Therapy; Cell surface; Cells; Chronic; Cicatrix; Collagen Fiber; Defect; Development; Disease; Elasticity; Exhibits; Extracellular Matrix; Future; Healed; Human; In Vitro; Injury; Lead; Measurement; Mechanics; Mesenchymal Stem Cells; Methods; Modeling; Molecular; Mus; Natural regeneration; Nature; Nuclear; Nuclear Receptors; Outcome; Outcome Study; Pain; Patients; Pharmaceutical Preparations; Physicians; Play; Population; Process; Production; Proliferating; Property; Proteoglycan; Recovery; Reporter; Retinoic Acid Receptor; Retinoids; Role; Rupture; Site; Stem cells; Tendon Injuries; Tendon structure; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transplantation; Visit; achilles tendon; design; effective therapy; flexibility; healing; high risk; improved; in vivo; injured; injury and repair; innovation; insight; new therapeutic target; novel; novel therapeutics; prevent; progenitor; public health relevance; repaired; research study; scleraxis; stem; success; tool; trait; translational medicine

DESCRIPTION (provided by applicant): There is an urgent need to create new and more effective therapies for tendon repair since injured tendons do not fully heal and regenerate. In acute tendon injuries, repair is carried out by intrinsic tendon cells and extrinsic cells that migrate from surrounding tissues and the circulation. The cells proliferate at the injured site, synthesize extracellular matrix, produce dense and aligned collagen fibers, and reorganize tendon structure to varying degrees. The repaired tendons can also undergo scarring and degeneration over time that are characterized by hypercellularity, mis-alignment and reduced number of collagen fibers, and increased production of cartilage-specific proteoglycans, among other defects. These alterations can result in loss of normal mechanical strength, flexibility and elasticity. It remains unclear as to which cells are responsible for the multistep repair process and which cellular actions should be enhanced or suppressed to prevent degenerative changes and improve healing. The elucidation of these and related issues could undoubtedly lead to development of new therapeutic tools to improve and stimulate tendon repair. We recently found that a cell population present at the injury site in mouse tendons exhibited progenitor-like traits including colony forming ability, multipotency and expression of mesenchymal stem cell surface markers. Interestingly, these injured tendon-associated progenitor cells, herein called inTPCs, possessed a much stronger ability to differentiate into chondrogenic cells than progenitor cells isolated from uninjured tendons. Furthermore, we found that agonists for the nuclear retinoic acid receptor ? (RAR?) stimulated tenogenic differentiation in cultured inTPCs, while they inhibited their chondrogenic differentiation in vitro and chondroid degeneration in ruptured mouse tendons in vivo. In addition, we found that mouse inTPCs participated in both repair process and degenerative changes in ruptured mouse tendons and that a similar cell population was present in injured human tendons. These and other results directly support and lead to our novel hypotheses that progenitor cells appearing in acutely injured tendons play important roles in tendon repair but also degeneration and that RAR? agonists can control their differential potential and improve tendon repair. This high risk-high return R21 project will test these novel possibilities using tendon progenitor cells in injured mouse and human tendons and will begin to develop methods to stimulate tendon repair by controlling differentiation of these progenitors toward a tenogenic lineage. Our aims are: (1) To determine the effects of RAR? agonists on inTPCs and tendon repair in a mouse tendon injury model; and (2) To determine whether human inTPCs contribute to repair and degenerative changes in injured tendons and respond to RAR? agonists. The outcome of these exploratory experiments will pave the way toward designing more encompassing projects in which the above therapeutic strategies and their underlying mechanisms of action can be studied in greater depth, leading to innovative translational medicine outcomes in tendon repair.

描述（由申请人提供）：由于受伤的肌腱无法完全愈合和再生，因此迫切需要创造新的、更有效的肌腱修复疗法。在急性肌腱损伤中，修复是由内在肌腱细胞和从周围组织和循环迁移的外在细胞进行的。细胞在受伤部位增殖，合成细胞外基质，产生致密且排列整齐的胶原纤维，并不同程度地重组肌腱结构。随着时间的推移，修复后的肌腱也会出现疤痕和退化，其特点是细胞增多、错位、胶原纤维数量减少、软骨特异性蛋白多糖产量增加等缺陷。这些改变会导致正常机械强度、柔韧性和弹性的丧失。目前尚不清楚哪些细胞负责多步骤修复过程，以及应该增强或抑制哪些细胞作用以防止退行性变化并改善愈合。对这些及相关问题的阐明无疑可以促进新的治疗工具的开发，以改善和刺激肌腱修复。我们最近发现，存在于小鼠肌腱损伤部位的细胞群表现出类似祖细胞的特征，包括集落形成能力、多能性和间充质干细胞表面标志物的表达。有趣的是，这些受伤的肌腱相关祖细胞（本文称为inTPC）比从未受伤的肌腱中分离的祖细胞具有更强的分化成软骨细胞的能力。此外，我们发现核视黄酸受体的激动剂？ (RAR?) 刺激 TPC 培养的肌腱分化，同时在体外抑制其软骨形成分化，在体内抑制破裂小鼠肌腱的软骨样变性。此外，我们发现小鼠 inTPC 参与了断裂的小鼠肌腱的修复过程和退行性变化，并且在受伤的人类肌腱中也存在类似的细胞群。这些和其他结果直接支持并导致我们的新假设，即急性损伤肌腱中出现的祖细胞在肌腱修复和退化中发挥重要作用，而RAR？激动剂可以控制其电位差并改善肌腱修复。这个高风险高回报的 R21 项目将使用受伤小鼠和人类肌腱中的肌腱祖细胞来测试这些新的可能性，并将开始开发通过控制这些祖细胞向肌腱谱系分化来刺激肌腱修复的方法。我们的目标是： (1) 确定 RAR 的效果？小鼠肌腱损伤模型中 inTPC 和肌腱修复的激动剂； (2) 确定人类 inTPC 是否有助于损伤肌腱的修复和退行性变化并对 RAR 做出反应？激动剂。这些探索性实验的结果将为设计更广泛的项目铺平道路，在这些项目中可以更深入地研究上述治疗策略及其潜在的作用机制，从而在肌腱修复方面产生创新的转化医学成果。