Facilitating meniscus healing through SDF-1/CXCR4 axis modified cell-therapy

通过 SDF-1/CXCR4 轴修饰细胞疗法促进半月板愈合

• 批准号: 10132243
• 负责人: Chathuraka Teekshana Jayasuriya
• 金额: $ 17.18万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132243
• 关键词: Adipocytes; Adipose tissue; Animal Model; Arthritis; Behavior; Biological; Biological Response Modifier Therapy; Biomechanics; Bone Marrow; CXCR4 Receptors; CXCR4 gene; Cartilage; Cell Therapy; Cells; Clinical; Data; Degenerative polyarthritis; Development; Engraftment; Fibrocartilages; Future; Gene Delivery; Gene-Modified; Goals; Histology; Human; Hypertrophy; In Vitro; Injury; Investigation; Joints; Knee; Knowledge; Literature; Measures; Mechanics; Medial meniscus structure; Mediating; Meniscus structure of joint; Mesenchymal; Mesenchymal Stem Cells; Mission; Modeling; Musculoskeletal; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural regeneration; Nature; Organism; Oryctolagus cuniculus; Patients; Pilot Projects; Public Health; Publishing; Reporting; Research; Research Design; Risk Factors; Rodent Model; Site; Solid; Stromal Cell-Derived Factor 1; Synovial Membrane; Testing; Tissues; United States National Institutes of Health; articular cartilage; base; chemokine receptor; disability; efficacy evaluation; healing; human DNA; improved; in vivo; injury and repair; innovation; joint injury; mechanical force; meniscal tear; meniscus injury; musculoskeletal injury; overtreatment; prevent; repair strategy; repaired; response; response to injury; scale up; stem; stem cells; tissue regeneration; tissue repair; trafficking

PROJECT SUMMARY/ABSTRACT Fibrocartilage tears in the avascular white-white zone of the meniscus are a significant clinical challenges due to their inability to heal. These common injuries are independent risk factors for the development of post-traumatic osteoarthritis. The long-term goal is to develop innovative cellular biologic therapies geared to stimulate healing of white-white zone meniscus tears in patients. Preliminary studies demonstrate that cartilage-derived mesenchymal progenitors (CPCs) can be used as a cell-therapy to effectively repair meniscus tears in a rodent model. However, since the long-term goal involves effectively treating human patients, there exists a knowledge gap as to how the beneficial healing effect of CPCs can be scaled up to in order to effectively repair menisci in larger animal models. The objective of this project to evaluate the efficacy of CXCR4 gene modified CPC therapy as a means of facilitating white-white zone tissue healing in a rabbit meniscus injury model. The central hypothesis is that treating white- white zone meniscus tears with CPCs that have elevated chemokine receptor CXCR4 will increase their cell localization to the site of injury and improve the extent and quality of the resulting healing response. This central hypothesis will be tested by completing two specific aims: (1) Measure the extent cell engraftment that results from gene delivery of CXCR4 into CPCs; (2) Evaluate the efficacy of meniscus repair resulting from CXCR4 gene modified cell therapy. The research design is to employ a gene delivery approach to modify the expression of the chemokine receptor CXCR4, which is a regulator cell trafficking in response to injury, in order to increase cell localization and engraftment to white-white zone meniscus injury sites. It is expected that this will improve meniscus injury repair as measured by biomechanical tensile testing and histology. Successful completion will have a positive impact by laying the groundwork for developing an effective new strategy to stimulate meniscus injury repair through the use of cellular biologics. This project is relevant to the mission of NIAMS because it seeks to find innovative ways to treat musculoskeletal injuries and prevent arthritis.

项目总结/摘要 半月板无血管白-白区的纤维软骨撕裂是一种重要的临床表现， 因为他们无法治愈。这些常见的损伤是独立的风险因素， 创伤后骨关节炎的发展。长远目标是发展创新 细胞生物疗法，旨在刺激白-白区半月板撕裂的愈合， 患者初步研究表明，软骨来源的间充质祖细胞 在啮齿动物模型中，CPC可用作细胞疗法以有效修复半月板撕裂。 然而，由于长期目标涉及有效地治疗人类患者，因此存在一种方法。 关于如何扩大CPC的有益治疗效果的知识差距，以便 在较大的动物模型中有效地修复脑梗死。本项目的目标是评估 CXCR 4基因修饰的CPC治疗作为促进白-白区的手段的功效 兔半月板损伤模型中的组织愈合。核心假设是治疗白色- 具有趋化因子受体CXCR 4升高的CPC的白色区半月板撕裂将 增加它们在损伤部位的细胞定位，并改善损伤的程度和质量。 导致愈合反应。这一中心假设将通过完成两个具体的 目的：（1）测量由CXCR 4基因递送引起的细胞植入到细胞中的程度。 （2）评价CXCR 4基因修饰细胞修复半月板的效果 疗法研究设计是采用基因递送方法来修饰表达 趋化因子受体CXCR 4是一种对损伤作出反应的调节细胞运输， 以增加白-白区半月板损伤部位的细胞定位和植入。是 预计这将改善半月板损伤修复，如生物力学拉伸测量 测试和组织学。成功完成将通过铺设 为开发有效的新策略以刺激半月板损伤修复奠定基础， 细胞生物学的应用。该项目与国家机构间监测系统的使命有关，因为它寻求 寻找治疗肌肉骨骼损伤和预防关节炎的创新方法。