Targeted Stem Cell Therapy Coupling Angiogenesis and Osteogenesis for Bone Defect

结合血管生成和骨生成的靶向干细胞治疗骨缺损

• 批准号: 8538294
• 负责人: Selvarangan Ponnazhagan
• 金额: $ 31.31万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538294
• 关键词: Address; Affect; Age; Area; Atrophic; Attention; BMP2 gene; Biological; Blood Circulation; Blood Vessels; Bone Density; Bone Marrow; Bone Regeneration; Bone remodeling; Cell Therapy; Cell Transplants; Cells; Clinical; Clinical Research; Complex; Coupling; Data; Defect; Development; Disease; Economic Burden; Ectopic Expression; Fracture; Genetic Engineering; Growth Factor; Healed; Healthcare; Home environment; Homing; Impaired wound healing; Injury; Integrins; Lead; Long-Term Effects; Lung; Mediating; Mesenchymal Stem Cells; Methods; Modality; Modeling; Molecular Medicine; Morbidity - disease rate; Multiple Fractures; Musculoskeletal System; Natural regeneration; Nature; Osteoblasts; Osteogenesis; Osteoporosis; Outcome Study; Pathology; Patients; Peripheral; Population; Recombinants; Regenerative Medicine; Role; Signal Pathway; Signal Transduction; Skeleton; Source; Stem cells; Stimulus; Testing; Therapeutic; Tissues; Transplantation; Treatment Efficacy; United States; Vascular Endothelial Growth Factors; Vascular blood supply; Vascular remodeling; angiogenesis; bone; bone healing; bone morphogenetic protein 2; effective therapy; healing; hypoxia inducible factor 1; improved; in vivo; mouse model; novel; novel therapeutic intervention; osteogenic; overexpression; pre-clinical; preclinical study; progenitor; regenerative; self-renewal; skeletal; stem cell therapy; tissue regeneration; tissue repair; treatment strategy

DESCRIPTION (provided by applicant): The potential of bone marrow-derived mesenchymal stem cells (MSC) in regenerative medicine is increasingly gaining attention. Among different tissues that can be regenerated using MSC, bone has greater potential for reasons including: MSC are the progenitor cells for bone-forming osteoblasts, and bone is the natural niche for MSC in the body. Thus, development of strategies to optimally use MSC should realize their potential in bone defects that are normally difficult to treat. One of the major problems in skeletal defects is the delayed healing or non-union of bone fractures. Demographic data reveal that due to the steadily rising age of the population, complications with the musculoskeletal system will increase during the coming years. Each year in the United States, there is an estimated six million fractures of which about 10% become non-union. Thus, new therapeutic approaches to successfully address this problem will hugely benefit health care and the economy. It is evident that the majority of aseptic non-union fractures require a variable degree of biological enhancement. Thus, new therapeutic approaches coupling angiogenesis to osteogenesis using MSC as genetically-engineered stem cell source will greatly advance patient management and reduce morbidity and economic burden. Despite the regenerative potential of MSC, one of the limitations in MSC therapy is target- specific homing of transplanted cells in vivo. We recently developed a method to enhance bone-specific homing of MSC by transient, ectopic expression of 1421 integrin. This strategy not only resulted in a significant increase in MSC homed to bone, but also greatly reduced the entrapment of MSC in the lungs. Using this targeting approach, we recently demonstrated that MSC, genetically-engineered to produce BMP2, significantly improved bone density during first few months in a mouse model of osteoporosis. Additional preliminary studies in a segmental bone defect from our lab using genetically-engineered MSC expressing VEGF demonstrated significant vascular remodeling. Results from these studies provide unique direction for the development of a new therapeutic approach for non-union fractures. In complicated fractures and non- unions, another reason that limits effective osteoinduction is the lack of MSC in sufficient numbers. Thus, strategies to enrich the MSC endogenously through peripheral mobilization and proliferation would greatly augment ossification. Such an approach will be ideal to treat non-union fractures and multiple fractures, which are also commonly encountered in patients with osteoporosis. An added advantage to the use of endogenous MSC in these pathologies is associated vascular damage, since MSC have also been shown to be effective in vascular regeneration. Combining these two aspects, the aims of the proposed studies is to test the effects of targeted stem cell therapy, coupling osteogenic and angiogenic inducers for non-union fractures in a preclinical mouse model, and to determine the therapeutic potential of peripheral mobilization and proliferation of endogenous MSC using growth factors and mobilization-inducing compounds. A positive outcome of these studies could lead to the development of new and effective treatment strategies for bone repair.

描述（申请人提供）：骨髓间充质干细胞（MSC）在再生医学中的潜力越来越受到关注。在可以使用MSC再生的不同组织中，骨具有更大的潜力，原因包括：MSC是骨形成成骨细胞的祖细胞，骨是MSC在体内的天然生态位。因此，发展战略，以最佳方式使用MSC应实现其潜力，在骨缺损，通常是难以治疗的。在骨骼缺损的主要问题之一是延迟愈合或骨折不愈合。人口统计数据显示，由于人口年龄的稳步上升，肌肉骨骼系统的并发症将在未来几年增加。在美国，每年估计有600万例骨折，其中约10%为骨不连。因此，成功解决这一问题的新治疗方法将极大地有利于医疗保健和经济。 很明显，大多数无菌性骨不连骨折需要不同程度的生物增强。因此，使用MSC作为基因工程干细胞来源将血管生成与骨生成偶联的新治疗方法将极大地推进患者管理并降低发病率和经济负担。尽管MSC具有再生潜力，但MSC疗法的限制之一是移植细胞在体内的靶特异性归巢。我们最近开发了一种方法，通过瞬时异位表达1421整合素来增强MSC的骨特异性归巢。这种策略不仅导致了MSC归巢到骨的显著增加，而且大大减少了MSC在肺中的截留。使用这种靶向方法，我们最近证明，MSC，基因工程产生BMP 2，显着提高骨密度在最初几个月内在骨质疏松症的小鼠模型。我们实验室使用表达VEGF的基因工程MSC对节段性骨缺损进行的其他初步研究显示了显著的血管重塑。这些研究结果为骨不连骨折的新治疗方法的发展提供了独特的方向。在复杂骨折和骨不连中，限制有效骨诱导的另一个原因是缺乏足够数量的MSC。因此，通过外周动员和增殖内源性富集MSC的策略将大大增加骨化。这种方法将是理想的治疗骨不连骨折和多发性骨折，这也是常见的骨质疏松症患者。在这些病理学中使用内源性MSC的另一个优点是相关的血管损伤，因为MSC也被证明在血管再生中有效。结合这两个方面，提出的研究的目的是测试靶向干细胞治疗的效果，在临床前小鼠模型中偶联成骨和血管生成诱导剂用于不愈合骨折，并确定使用生长因子和动员诱导化合物的内源性MSC的外周动员和增殖的治疗潜力。这些研究的积极结果可能会导致开发新的有效的骨修复治疗策略。