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 初始化。 治疗 基本 小说 先前 位于 维护使用 Gli 1-CreER驱动的Hh报告基因小鼠系，我们最近发现Gli 1标记的细胞有助于 半月板角从2周龄开始发育。在成年和老年小鼠中，Gli 1+细胞定位于 前、后翼角浅层的数量随年龄增长而逐渐减少。 在体内，这些细胞共表达间充质祖细胞的已知标志物以及润滑剂Prg 4。在 体外培养的胶质细胞Gli 1+细胞具有较高的祖细胞活性，如增殖、迁移和增殖能力， 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 Gli 1系细胞在前角损伤部位迅速扩增。这些Gli 1+细胞的消融， 损伤延缓了半月板修复过程。引人注目的是，关节内注射Hh激活剂， 损伤后，Purmorphamine（Pur）加速半月板修复并减弱OA进展。基于 根据这些数据，我们假设Hh/Gli 1通路可以作为治疗半月板损伤的靶点 撕裂是膝盖最常见的损伤，影响年轻人和老年人。 然而，愈合是有限的，并且功能丧失导致软骨丧失和骨关节炎。 目前的临床治疗是姑息性的，不能恢复功能，也没有疾病改善药物 可用于半月板损伤的治疗。因此，迫切需要更好地了解 调节半月板稳态和修复的生物机制和途径， 治疗学间充质祖细胞在组织维持和再生中起关键作用。 研究已经证明半月板中存在间充质祖细胞，其中大多数 在表层内。Hedgehog（Hh）信号传导是少数几个基本途径之一， 成体干细胞和祖细胞在各种器官中，并且可以在损伤后激活这些细胞。 试验），测试 并通过动员内源性半月板祖细胞防止OA发展。 工作 设计 旨在 评价 支架介导 这一目标 是为了了解这种新的信号通路在半月板稳态和修复中的作用， 一种通过局部靶向该途径来增强半月板修复的新型药物递送系统。我们的具体 目的是：1）确定Hh信号传导在半月板发育和修复中的功能; 2）合成和 用于半月板修复的纳米颗粒（NP）缀合的纤维递送系统; 3）评估Pur-NP 半月板损伤大型动物模型的修复。小型（小鼠）和大型（小型猪）动物 模型和补充实验工具将用于开发和转化这种新疗法。 多学科 如果成功，这项工作将 愈合 我们 团队共同努力，产生了令人兴奋的初步数据，支持这一建议。 提供了一种新的治疗支架， 被认为是无法挽回的眼泪 如果