Stem Cell-Derived Extracellular Vesicles for Enhanced Tendon Healing

干细胞衍生的细胞外囊泡可增强肌腱愈合

• 批准号: 9896363
• 负责人: Hua Shen
• 金额: $ 20.74万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896363
• 关键词: Accounting; Acute; Adipose tissue; Adult; Area; Attenuated; Biological Response Modifier Therapy; Biomechanics; Cells; Clinical; Clinical Research; Coculture Techniques; Collagen; Data; Disease; Economics; Engineering; Exhibits; Failure; Gene Expression; Genes; Goals; Health; Histology; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Lead; Luciferases; Mediating; Membrane; Methods; MicroRNAs; Modeling; Molecular; Mus; Musculoskeletal; Natural regeneration; Operative Surgical Procedures; Orthopedics; Outcome; Pathway interactions; Phase; Phenotype; Physical Function; Process; Production; Proteins; RNA; Regenerative Medicine; Rehabilitation therapy; Reporter; Reporting; Research; Role; Safety; Signal Transduction; Site; Stem cells; Stimulus; Structure; Techniques; Tendon Injuries; Tendon structure; Testing; Therapeutic; Therapeutic Agents; Tissues; Treatment Efficacy; United States; achilles tendon; adult stem cell; base; clinically relevant; cost; cytokine; design; extracellular vesicles; healing; improved; in vivo; injured; injury and repair; innovation; insight; intercellular communication; ligament injury; macrophage; monocyte; musculoskeletal injury; nanoparticle; nanosized; primary outcome; recruit; regenerative; repaired; response; social; soft tissue; surgery outcome; tissue repair; transcriptome sequencing; translational study

PROJECT SUMMARY/ABSTRACT Tendon and ligament injuries account for nearly half of all musculoskeletal injuries each year in the United States. Even with considerable improvements, surgical repairs do not consistently restore physical function of injured tissues. As a result, there are lengthy delays or failures to return to pre-injury activities, thus posing a substantial clinical, economic and social burden. Poor surgical outcomes primarily result from excessive inflammation and insufficient regeneration of repaired tissues. Therefore, the long-term goal of this study is to develop biologic therapies to enhance tendon repair. With recent advances in regenerative medicine and extracellular vesicle (EV) research, the proposed project has been designed to investigate the mechanistic role and clinically relevant application of stem cell EVs in tendon repair. EVs are membrane-enclosed nanoparticles that mediate intercellular communication by transferring bioactive molecules (proteins, RNAs, etc.) from cell to cell. Although EVs from adipose-derived stem cells (ASCs) have been found to modulate tissue inflammatory response and to promote regeneration of some soft tissues, their role in tendon repairs has not been directly explored. Aim 1 will use co-culture models to determine the role and underlying molecular mechanism of ASC EVs in regulating macrophage inflammatory response and tenocyte activity and function in the context of tendon injury and repair. Aim 2 will use a clinically relevant mouse Achilles tendon injury and repair model to determine the therapeutic efficacy of ASC EVs in reducing inflammation, increasing tendon matrix regeneration and restoring structure and strength of injured tendons. Results from Aim 1 will reveal new insights into the mechanism of ASC EVs in regulating tendon healing process and provide guidance for further engineering of defined components within ASC EVs to provide improved therapeutic efficacy and safety. Positive outcomes from Aim 2 will prove the concept of ASC EV-based therapy for tendon injury as well as other related disorders and lead to clinical studies, thus contributing to the improvement of musculoskeletal health.

项目摘要/摘要 肌腱和韧带损伤占联合每年所有肌肉骨骼损伤的几乎一半 国家。即使有了很大的改进，手术维修也不会持续恢复 受伤的组织。结果，有很长的延误或未能返回受伤前活动，从而提出 实质性的临床，经济和社会负担。手术结果不佳，主要是由于过度而导致的 修复组织的炎症和再生不足。因此，这项研究的长期目标是 开发生物疗法以增强肌腱修复。随着再生医学的最新进展和 细胞外囊泡（EV）研究，拟议的项目旨在研究机械作用 干细胞电动汽车在肌腱修复中的临床相关应用。电动汽车是膜封闭的纳米颗粒 通过将生物活性分子（蛋白质，RNA等）从细胞转移到细胞间通信 细胞。尽管已经发现来自脂肪衍生的干细胞（ASC）的电动汽车调节组织炎症 反应并促进某些软组织的再生，它们在肌腱维修中的作用尚未直接 探索。 AIM 1将使用共培养模型来确定ASC的作用和潜在分子机制 在调节巨噬细胞炎症反应和养细胞活性和功能中的电动汽车在 肌腱损伤和修复。 AIM 2将使用临床上相关的小鼠跟腱损伤和修复模型 确定ASC电动汽车在减少炎症，增加肌腱基质再生中的治疗功效 并恢复受伤肌腱的结构和强度。 AIM 1的结果将揭示对 ASC电动汽车在调节肌腱愈合过程中的机制，并为进一步的工程提供指导 ASC内电动汽车内定义的组件可提高治疗功效和安全性。积极的结果 来自AIM 2将证明基于ASC EV的肌腱损伤疗法以及其他相关疾病的概念 并导致临床研究，从而有助于改善肌肉骨骼健康。