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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：骨髓来源的间充质干细胞（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，骨骼具有更大的潜力，其原因包括：MSC是用于骨形成骨细胞的祖细胞，而骨骼是体内MSC的天然利基市场。因此，开发最佳使用MSC的策略应在通常难以治疗的骨缺陷中实现其潜力。骨骼缺陷的主要问题之一是骨折的延迟愈合或非工会。人口统计数据表明，由于人口年龄的稳定增长，在未来几年中，肌肉骨骼系统的并发症将增加。每年在美国，估计有600万个骨折，其中约10％成为非工会。因此，成功解决此问题的新治疗方法将极大地使医疗保健和经济受益。显然，大多数无菌性非工会骨折都需要变化的生物学增强。因此，使用MSC作为基因设计的干细胞来源将血管生成与成骨的新治疗方法将大大提高患者的管理并减轻发病率和经济负担。尽管MSC的再生潜力，但MSC治疗的局限性之一是体内移植细胞的靶标归位。我们最近开发了一种通过1421整联蛋白的瞬时异位表达来增强MSC骨特异性归巢的方法。该策略不仅导致MSC大量增加到骨骼，而且大大减少了MSC在肺中的夹带。使用这种靶向方法，我们最近证明，在骨质疏松小鼠模型中，在最初几个月中，遗传工程生产BMP2的MSC显着提高了骨密度。使用遗传学的MSC表达VEGF的MSC在我们实验室的分段骨缺陷中进行了其他初步研究，表现出明显的血管重塑。这些研究的结果为开发非工会骨折的新治疗方法提供了独特的方向。在复杂的裂缝和非工会中，限制有效骨诱导的另一个原因是缺乏足够数量的MSC。因此，通过周围动员和增殖来富集MSC的策略将大大增加骨化。这种方法将是治疗非工会骨折和多种骨折的理想选择，骨质疏松症患者通常也遇到这些骨折。在这些病理中使用内源性MSC的额外优势是相关的血管损伤，因为MSC也已被证明在血管再生中有效。结合了这两个方面，提出的研究的目的是在临床前小鼠模型中测试靶向干细胞疗法，偶联的成骨和血管生成诱导剂对非工会骨折的影响，并确定外周种动员的治疗潜力以及使用内源性MSC使用生长因子和生长因素和动员化合物 - 诱导的诱导性。这些研究的积极结果可能导致发展新的有效的骨修复治疗策略。