Stem Cell-Derived Extracellular Vesicles for Enhanced Tendon Healing

项目摘要/摘要 肌腱和韧带损伤占美国每年所有肌肉骨骼损伤的近一半 各州。即使有相当大的改善，手术修复也不能始终如一地恢复膝关节的物理功能。 受伤的组织。结果，恢复到受伤前的活动有很长的延误或失败，从而造成了 巨大的临床、经济和社会负担。手术结果不佳主要是由于过度 修复后的组织发炎和再生不足。因此，这项研究的长期目标是 开发生物疗法以促进肌腱修复。随着再生医学和 细胞外小泡(EV)的研究，该项目的提出旨在调查其机制作用 干细胞EVS在肌腱修复中的临床应用。电动汽车是膜包裹的纳米颗粒 通过转移生物活性分子(蛋白质、RNA等)来调节细胞间的通讯。从单元格到 手机。尽管已经发现来自脂肪干细胞(ASCs)的EV可以调节组织炎症 反应和促进一些软组织的再生，它们在肌腱修复中的作用并不直接 探索过了。目标1将使用共培养模型来确定ASC的作用和潜在的分子机制 EVS在调节巨噬细胞炎症反应和肌腱细胞活性和功能中的作用 肌腱损伤和修复。Aim 2将使用临床相关的小鼠跟腱损伤和修复模型来 确定ASC EVS在消炎、促进肌腱基质再生方面的疗效 恢复损伤肌腱的结构和强度。来自AIM 1的结果将揭示对 ASC EVS调控肌腱愈合过程的机制为进一步工程化肌腱提供指导 在ASC电动汽车内定义的组件，以提供更好的治疗效果和安全性。积极的结果 目标2将证明基于ASC EV的肌腱损伤和其他相关疾病治疗的概念 并引导临床研究，从而有助于改善肌肉骨骼健康。

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.