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: 8087215
• 负责人: Selvarangan Ponnazhagan
• 金额: $ 32.96万
• 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/8087215
• 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; Engineering; 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; Wound Healing; 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; 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. PUBLIC HEALTH RELEVANCE: A major problem in skeletal defects is non-union of bone fractures. The potential of bone marrow- derived mesenchymal stem cells (MSC) in regenerative medicine is increasingly gaining attention especially for diseases affecting the skeleton since 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 non-union bone defects, which are difficult to treat.

描述（由申请人提供）：骨髓间充质干细胞（MSC）在再生医学中的潜力日益受到关注。在可以利用间充质干细胞再生的不同组织中，骨骼具有更大的潜力，原因包括：间充质干细胞是成骨成骨细胞的祖细胞，而骨骼是间充质干细胞在体内的天然生态位。因此，制定最佳使用间充质干细胞的策略应该能够实现它们在通常难以治疗的骨缺损方面的潜力。骨骼缺陷的主要问题之一是骨折延迟愈合或不愈合。人口统计数据显示，由于人口年龄的稳步增长，未来几年肌肉骨骼系统的并发症将会增加。在美国，每年估计有 600 万例骨折，其中约 10% 发生骨折不愈合。因此，成功解决这一问题的新治疗方法将极大地有益于医疗保健和经济。 显然，大多数无菌骨不连骨折需要不同程度的生物增强。因此，使用间充质干细胞作为基因工程干细胞来源，将血管生成与成骨结合起来的新治疗方法将极大地促进患者管理，降低发病率和经济负担。尽管 MSC 具有再生潜力，但 MSC 治疗的局限性之一是移植细胞在体内的目标特异性归巢。我们最近开发了一种通过 1421 整合素的瞬时异位表达来增强 MSC 骨特异性归巢的方法。这一策略不仅导致归巢于骨骼的 MSC 显着增加，而且还大大减少了 MSC 在肺部的滞留。使用这种靶向方法，我们最近证明，通过基因工程产生 BMP2 的 MSC 在骨质疏松症小鼠模型的最初几个月内显着改善了骨密度。我们的实验室使用表达 VEGF 的基因工程 MSC 对节段性骨缺损进行了额外的初步研究，证明了显着的血管重塑。这些研究的结果为开发治疗不愈合骨折的新方法提供了独特的方向。在复杂的骨折和骨不连中，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来内源性富集 MSC 的策略将极大地促进骨化。这种方法非常适合治疗骨不连骨折和多发性骨折，这在骨质疏松症患者中也很常见。在这些病理学中使用内源性 MSC 的另一个优势是与血管损伤相关，因为 MSC 也已被证明对血管再生有效。结合这两个方面，拟议研究的目的是在临床前小鼠模型中测试靶向干细胞治疗、耦合成骨和血管生成诱导剂对骨不连骨折的效果，并确定使用生长因子和动员诱导化合物外周动员和内源性 MSC 增殖的治疗潜力。这些研究的积极成果可能会导致开发新的有效的骨修复治疗策略。 公众健康相关性：骨骼缺陷的一个主要问题是骨折不愈合。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，特别是对于影响骨骼的疾病，因为 MSC 是成骨成骨细胞的祖细胞，而骨骼是 MSC 在体内的天然生态位。因此，制定最佳使用 MSC 的策略应该能够实现其在难以治疗的骨不连缺损中的潜力。