Activation of endogenous progenitors via a nanoparticle-conjugated fibrous system to enhance meniscus repair

通过纳米颗粒共轭纤维系统激活内源祖细胞以增强半月板修复

• 批准号: 10607306
• 负责人: Robert L Mauck
• 金额: $ 47.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-20 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607306
• 关键词: Ablation; Acceleration; Adult; Affect; Aftercare; Age; Aging; Animal Model; Anterior; Antibodies; Attenuated; Biological; Biology; Cartilage; Cell Lineage; Cell physiology; Cells; Chemistry; Clinical Treatment; Data; Degenerative polyarthritis; Development; Disease; Dose; Drug Delivery Systems; Erinaceidae; Excision; Family suidae; Femur; Fibrocartilages; Goals; Health; Heterogeneity; Homeostasis; Horns; Human; Injury; Intra-Articular Injections; Joints; Knee; Knee Injuries; Knee Osteoarthritis; Knowledge; Label; Lubricants; Lubrication; Maintenance; Mechanics; Mediating; Meniscus structure of joint; Mesenchymal Stem Cells; Metabolism; Miniature Swine; Modeling; Mus; Nanotechnology; Natural regeneration; Older Population; Oligonucleotides; Operative Surgical Procedures; Organ; Pain management; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Play; Procedures; Process; Proliferating; Reporter; Role; Shock; Signal Pathway; Signal Transduction; Site; Structure; Surgical Management; Surgical sutures; System; Testing; Therapeutic; Thick; Tissues; Translating; Work; absorption; aged; aging population; cell motility; design; fabrication; gain of function; healing; improved; in vivo; innovation; loss of function; meniscal tear; meniscus injury; migration; mouse model; multidisciplinary; nanoparticle; nanoparticle delivery; novel; novel therapeutic intervention; novel therapeutics; palliative; preservation; prevent; progenitor; purmorphamine; recruit; repair function; repaired; response; response to injury; scaffold; single-cell RNA sequencing; smoothened signaling pathway; spatiotemporal; stem; stem cells; systemic barrier; therapeutic target; tibia; tool

Project Summary Meniscus Meniscus initiation. therapy basic novel Previous located maintain Using a Gli1-CreER driven Hh reporter mouse line, we recently found that Gli1-labeled cells contribute to the development of the meniscus horns from 2 weeks of age. In adult and aged mice, Gli1+ cells were localized to the superficial layer of anterior and posterior meniscal horns, and gradually decreased in number during aging. In vivo, these cells co-expressed known markers of mesenchymal progenitors as well as the lubricant Prg4. In culture, meniscal Gli1+ cells possessed high progenitor activities, such as proliferation, migration, and differentiation, under the control of Hh signal. Using an in vivo mouse meniscus injury model, we showed a rapid expansion of Gli1-lineage cells at the injury site of anterior horn. Ablation of these Gli1+ cells prior to injury slowed the meniscus repair process. Strikingly, intra-articular injection of the Hh activator, Purmorphamine (Pur), following injury accelerated meniscus repair and attenuated OA progression. Based on these data, we hypothesize that the Hh/Gli1 pathway can be therapeutically targeted to treat meniscus injury tears are the most common injury to the knee, affecting both young and old populations. healing is limited, however, and loss of function leads o cartilage loss and osteoarthritis OA) Current clinical treatment is palliative, and does not restore function, and no disease modifying drug is available for the t reatment of meniscus injury. Thus, there is a critical need to better understand the biologic mechanisms and pathways regulating meniscus homeostasis and repair in order to develop therapeutics. Mesenchymal progenitors play a critical role in tissue maintenance and regeneration. studies have demonstrated the existence of mesenchymal progenitors in the meniscus, with most within the superficial layer. Hedgehog (Hh) signaling is one of a few fundamental pathways that adult stem and progenitor cells in various organs and can activate these cells post injury. t ( and prevent OA development via the mobilization of endogenous meniscus progenitors. work design Aims evaluate scaffold-mediated The objectives of this are to understand the role of this novel signaling pathway in meniscus homeostasis and repair and to a novel drug delivery system to enhance meniscus repair by locally targeting t his pathway. Our specific are to: 1) determine the function of Hh signaling in meniscus development and repair; 2) synthesize and a nanoparticle (NP)-conjugated fibrous delivery system for meniscus repair; 3) Assess Pur-NP repair in a large animal model of meniscus injury.Small (mouse) and large (minipig) animal models, and complementary experimental tools will be utilized to develop and translate this new therapy. multidisciplinary successful, this work will healing Our team has worked together to generate the exciting preliminary data supporting this proposal. provide a novel therapeutic scaffold that mobilizes meniscus progenitors to improve of tears that are otherwise considered irreparable. If

项目摘要 半月板 半月板 引发。 治疗 基本的 小说 以前的 位于 使用A。 Gli1-creer驱动的HH记者小鼠系列，我们最近发现Gli1标记的细胞有助于该细胞 从2周龄开始的弯弯角喇叭的发展。在成年小鼠和老年小鼠中，Gli1+细胞定位于 前半月板角的浅表层，在衰老过程中逐渐减少。 在体内，这些细胞共表达了间充质祖细胞和润滑剂PRG4的已知标记。在 培养，半月板GLI1+细胞具有较高的祖细胞活性，例如增殖，迁移和 分化，在HH信号的控制下。使用体内小鼠半月板损伤模型，我们显示了一个 Gli1-linege细胞在前角的损伤部位快速扩张。在这些Gli1+细胞之前消融 伤害减慢了弯月板修复过程。令人惊讶的是，HH激活剂的关节内注射， 受伤加速弯月板修复并减弱OA进展后，呼吸肾上腺素（PUR）。基于 这些数据，我们假设可以将HH/GLI1途径用于治疗半月板损伤 眼泪是膝盖最常见的伤害，影响了年轻人和老年人。 但是，愈合受到限制，功能丧失导致软骨损失和骨关节炎OA） 当前的临床治疗是姑息治疗的，不会恢复功能，也没有改变药物的疾病 可用于半月板损伤的治疗。因此，迫切需要更好地了解 调节半月板稳态和维修以发展的生物机制和途径 疗法。间充质祖细胞在组织维持和再生中起关键作用。 研究表明，弯板中存在间充质祖细胞，大多数 在浅层层中。刺猬（HH）信号传导是少数几种基本途径之一 各种器官中的成年茎和祖细胞，可以在损伤后激活这些细胞。 t（ 并通过动员内源半月板祖细胞来防止OA发展。 工作 设计 目标 评价 脚手架介导的 目标的目标 要了解这种新颖的信号通路在半月板稳态和维修中的作用 一种新型的药物输送系统，可通过局部瞄准他的途径来增强半月板修复。我们的具体 为：1）确定HH信号在半月板开发和修复中的功能； 2）合成和 纳米颗粒（NP）偶联的纤维递送系统，用于弯弯曲修复； 3）评估pur-np 在半月板损伤的大动物模型中修复。 模型和互补的实验工具将用于开发和翻译这种新疗法。 多学科 成功，这项工作将 康复 我们的 团队共同努力，生成了支持该建议的令人兴奋的初步数据。 提供一种新型的治疗脚手架，可动员半月板祖细胞改善 泪水被认为是无法弥补的。 如果