Intrasynovial soft tissue healing - a novel translational goal for mesenchymal stem cell therapy

滑膜内软组织愈合——间充质干细胞治疗的新转化目标

• 批准号: MR/J006815/1
• 负责人: Roger Smith
• 金额: $ 71.96万
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ006815%2F1
• 关键词: Intrasynovial; soft; tissue; healing; novel

Shoulder pain in very common in humans, of which the most common cause is a tear to a complex arrangement of tendons in the shoulder known as the 'rotator cuff'. Signs include shoulder pain and an inability to raise the arm above the head. These injuries occur as part of an age-related degenerative process and current treatments, frequently involving the injection of corticosteroids into the area, have been shown to be largely ineffective in the long term, even though they can produce short-term pain relief. Surgical repairs of persistent and severe rotator cuff tears are expensive and also frequently fail. There is therefore a need to improve methods of treating this very common condition. One of the leading candidates to provide this extra impetus to achieve functional repair is the use of stem cell therapy. We have recently shown that the use of adult stem cells (known as mesenchymal stem cells) brings apparent clinical benefit in the treatment of equine overstrain tendon injuries and so we propose to deliver live stem cells from the same individual who has the injury, prepared from two different but clinically practical sources - from the bone marrow or from the synovial cells within, or lining, the cavity in which the tendon lies. These cells could be easily delivered either by injection or at the time of surgery. This project tests the hypothesis that the administration of stem cells will improve the healing of tendons inside a synovial environment. It will use a large animal experimental model with similarities to the natural disease in humans to support a subsequent (if the project is successful) application to undertake a 'first-in-man' clinical trial after the conclusion of the project.The project is composed of two complimentary, but not inter-dependent, project phases. The first will investigate, in the laboratory, the effects of stem cells on tendon sections in a culture dish. This will allow us to determine optimal dosages, compare the performance of the different cell types, and evaluate two possible mechanisms of action - the ability of the cells to 'seal' the surface of a damaged tendon and to actively heal it - which has enabled us to limit the number of animals needed in the second phase of the study. Here we will use a novel, recently validated, but more highly relevant, cost-effective model in the sheep. This model consists of a reproducible surgical defect in a tendon created by key-hole surgery which does not result in significant discomfort post-operatively but does produce a similar lack of healing to that seen in rotator cuff disease. The use of a 'large animal' model also enables us to use cells prepared from the same animal in a manner identical to that proposed for use in humans thereby making it most relevant to inform the early translation of the technology subsequently for human medical use.

肩部疼痛在人类中很常见，其中最常见的原因是肩部复杂的肌腱（称为“肩袖”）撕裂。症状包括肩部疼痛和无法将手臂举过头顶。这些损伤是与年龄相关的退行性过程的一部分，目前的治疗方法，经常涉及到在该区域注射皮质类固醇，尽管它们可以产生短期的疼痛缓解，但从长期来看，它们基本上是无效的。手术修复持续性和严重的肩袖撕裂是昂贵的，也经常失败。因此，有必要改进治疗这种非常常见的疾病的方法。为实现功能修复提供额外动力的主要候选方法之一是使用干细胞疗法。我们最近的研究表明，使用成体干细胞（称为间充质干细胞）在治疗马肌腱过度劳损损伤方面带来了明显的临床益处，因此我们建议使用来自同一受伤个体的活干细胞，从两种不同但临床上实用的来源制备-来自骨髓或来自肌腱所在腔内或衬里的滑膜细胞。这些细胞可以很容易地通过注射或在手术时传递。这个项目测试了一个假设，即干细胞的施用将改善滑膜环境中肌腱的愈合。它将使用与人类自然疾病相似的大型动物实验模型，以支持在项目结束后（如果项目成功）进行“首次人体”临床试验的后续申请。项目由两个互补但不相互依赖的项目阶段组成。第一项研究将在实验室中研究干细胞对培养皿中肌腱切片的影响。这将使我们能够确定最佳剂量，比较不同细胞类型的性能，并评估两种可能的作用机制——细胞“密封”受损肌腱表面和主动愈合肌腱的能力——这使我们能够限制第二阶段研究所需的动物数量。在这里，我们将使用一种新颖的，最近验证的，但更高度相关的，具有成本效益的羊模型。该模型由锁眼手术造成的肌腱可复制的手术缺陷组成，该手术不会导致术后明显的不适，但会产生与肩袖疾病相似的愈合不足。使用“大型动物”模型还使我们能够以与建议用于人类的方式相同的方式使用从同一动物制备的细胞，从而使其与随后将该技术用于人类医疗用途的早期翻译最相关。

项目成果

Author Correction: Pathogenic stromal cells as therapeutic targets in joint inflammation.

作者更正：致病性基质细胞作为关节炎症的治疗靶点。

• DOI: 10.1038/s41584-018-0134-1
• 发表时间: 2019
• 期刊: Nature reviews. Rheumatology
• 作者: Dakin SG

Exposure of a tendon extracellular matrix to synovial fluid triggers endogenous and engrafted cell death: A mechanism for failed healing of intrathecal tendon injuries

• DOI: 10.1080/03008207.2016.1245726
• 发表时间: 2017-01-01
• 期刊: CONNECTIVE TISSUE RESEARCH
• 影响因子: 2.9
• 作者: Garvican, Elaine R.;Salavati, Mazdak;Dudhia, Jayesh
• 通讯作者: Dudhia, Jayesh