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 入会仪式。 治疗法 基础版 小说 上一首 设于 维护时使用 Gli1-Creer驱动的HH报告鼠系，我们最近发现Gli1标记的细胞对 半月板角从2周龄开始发育。在成年和老年小鼠中，Gli1+细胞定位于 半月板前角和后角的浅层，随着年龄的增长逐渐减少。 在体内，这些细胞共表达已知的间充质祖细胞标志物以及润滑剂Prg4。在……里面 培养的半月板Gli1+细胞具有较高的祖细胞活性，如增殖、迁移和 分化，在HH信号的控制下。使用活体小鼠半月板损伤模型，我们展示了 前角损伤部位Gli1系细胞的快速扩增。对这些Gli1+细胞进行消融 损伤减缓了半月板的修复过程。引人注目的是，关节内注射了HH激活剂， 损伤后应用扑尔法明可加速半月板修复，延缓骨性关节炎的进展。基于 这些数据，我们假设HH/Gli1通路可以作为治疗的靶点来治疗半月板损伤 泪水是膝盖最常见的损伤，年轻人和老年人都会受到影响。 然而，愈合是有限的，功能丧失会导致软骨丢失和骨关节炎。 目前的临床治疗是姑息性的，不能恢复功能，也没有疾病改良药 可用于半月板损伤的治疗。因此，迫切需要更好地理解 调节半月板动态平衡和修复的生物学机制和途径 治疗学。间充质祖细胞在组织维持和再生中起着关键作用。 研究表明，半月板中存在间充质祖细胞，大多数 在表层内。Hedgehog(HH)信号是为数不多的几条基本途径之一 成体干细胞和前体细胞存在于各种器官中，并能在损伤后激活这些细胞。 T( 并通过动员内源性半月板前体细胞来预防骨性关节炎的发生。 工作 设计 目标 评估 脚手架中介 这样做的目的是 了解这一新的信号通路在半月板稳态和修复中的作用，以及 一种通过局部靶向半月板通路促进半月板修复的新型给药系统。我们的特定 目的是：1)确定HH信号在半月板发育和修复中的作用；2)合成和 用于半月板修复的纳米颗粒(NP)-偶联纤维递送系统；3)评价PUR-NP 半月板损伤大动物模型的修复。小(鼠)和大(小型)猪 将利用模型和补充的实验工具来开发和翻译这一新疗法。 多学科 如果成功，这项工作将 愈合 我们的 团队已经共同努力，生成了支持这一提议的令人兴奋的初步数据。 提供一种新型的治疗支架，动员半月板祖细胞改善 那些原本被认为无法挽回的泪水。 如果