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其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表明，血管重塑显着。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疗法、耦合成骨和血管生成诱导剂对不愈合骨折的效果，并确定外周动员和增殖的治疗潜力。使用生长因子和动员诱导化合物的内源性 MSC。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。