Adult Multipotent Mesenchymal Stromal Cells for Fracture Repair

用于骨折修复的成体多能间充质基质细胞

• 批准号: 8322801
• 负责人: Anna Spagnoli
• 金额: $ 30.4万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-05 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322801
• 关键词: Adult; Affect; Biomechanics; Bone Marrow; Bone Transplantation; Bone callus; CXC Chemokines; Cell Therapy; Cell physiology; Cells; Cessation of life; Clinical; Data; Development; Economics; Elderly; Engraftment; Environment; Foundations; Fracture; Fracture Healing; Genetically Engineered Mouse; Goals; Grant; Harvest; Healed; Homing; Hospitalization; In Vitro; Incidence; Injury; Insulin-Like Growth Factor I; Investigation; Laboratories; Lead; Ligands; Mediating; Mesenchymal; Mesenchymal Differentiation; Mesenchymal Stem Cells; Methods; Modeling; Morbidity - disease rate; Osteoblasts; Osteogenesis; Osteoporosis; Patients; Population; Procedures; Process; Property; Proto-Oncogene Proteins c-akt; Publishing; Regenerative Medicine; Regulation; Reporting; Research; Reticular Cell; Role; Seeds; Signal Pathway; Signal Transduction; Site; Soil; Speed; Staging; Stem cells; Stromal Cells; Testing; Time; Tissues; Transplantation; Transplanted tissue; United States; Vascular Endothelial Growth Factors; age related; autocrine; base; bone cell; bone morphogenic protein; bone strength; cell type; chemokine receptor; cost; fascinate; healing; improved; in vivo; injured; insight; interest; mouse model; multipotent cell; novel; novel therapeutic intervention; osteoblast differentiation; osteogenic; paracrine; progenitor; programs; public health relevance; regenerative; repaired; social; stem; tissue regeneration

DESCRIPTION (provided by applicant): Fracture injuries represent a significant clinical burden, with up to 6.2 million fractures occurring annually in the United States alone, of which 10% are complicated by non-unions. Current methods for treatment of non- unions with bone grafts have been fraught with multiple shortcomings, leading to an urgent and unmet need for alternative approaches. Adult bone marrow (BM) contains multipotent mesenchymal stromal cells (MSC) that have all the properties to become a novel therapeutic approach to treat non-unions. MSC have ample regenerative abilities via their multilineage, end-stage mesenchymal cell type differentiation potential (autocrine effect) and through secretion of bioactive molecules that regulate the regenerative microenvironment of an injured tissue (autocrine effect). During the first cycle of this grant, our laboratory has reported in several published investigations the in vivo dynamics of MSC after transplant, their engraftment within a specific fracture callus endosteal niche where they express bone morphogenic protein-2 (BMP-2) and their beneficial effects on fracture tissue healing and strength. We have also found that transplanted MSC expressing insulin- like growth factor-I (IGF-I) differentiate into bone cells within the fracture callus and promote fracture healing by inducing more new bone formation than MSC alone. The central hypothesis of this proposal is that MSC improve the fracture repair process by promoting a regenerative microenvironment through autocrine and paracrine actions. Specifically, we propose the following: Specific Aims1, to determine whether MSC improve the fracture repair process through induction of BMP-2 expression; Specific Aim 2, to determine whether MSC programmed to express IGF-I improve fracture healing by promoting bone formation through autocrine and paracrine mechanisms. Our results will open novel perspectives that will allow the full appreciation of the regenerative capacities of MSC and therefore set new research directions in the field of regenerative medicine. A comprehensive approach that combines in vivo and in vitro studies on genetically engineered mice, mouse models for non-unions and novel methods to assess fracture healing will be applied to accomplish the proposed aims. Studies would have major biomedical relevance and implications, as they lead to a better understanding of the mechanisms through which MSC promote fracture repair that will set the foundation for the development of novel MSC-based therapies to promote fracture healing in patients with non-unions. PUBLIC HEALTH RELEVANCE: Non-union fractures remain a challenging clinical problem that affect approximately 600,000 people every year in the United States. Because our elderly population is becoming larger, an increased incidence of non- unions as consequence of poor healing and age-related worsening of osteoporosis is expected. Adult bone marrow contains multipotent mesenchymal stromal cells (MSC) that have all the properties to become a novel therapeutic approach to treat non-unions. The overall goal of this proposal is to understand the mechanisms through which MSC exert their beneficial effects in fracture repair. Unraveling how MSC are capable to respond to the fracture regenerative clue and to provide the adequate environment for tissue regeneration will provide critical insights to develop novel MSC-based therapies to treat patients with non-unions

描述（由申请人提供）：骨折损伤是一个重大的临床负担，仅在美国每年就发生多达620万例骨折，其中10%并发骨不连。目前用骨移植物治疗骨不连的方法充满了多种缺点，导致对替代方法的迫切和未满足的需求。成人骨髓（BM）含有多能间充质基质细胞（MSC），这些细胞具有成为治疗骨不连的新型治疗方法的所有特性。MSC通过其多谱系、终末期间充质细胞类型分化潜力（自分泌效应）和通过分泌调节受损组织的再生微环境的生物活性分子（自分泌效应）而具有充足的再生能力。在第一轮资助期间，我们的实验室在几项已发表的研究中报告了移植后MSC的体内动力学，它们在特定骨折骨痂骨内膜龛内的植入，在那里它们表达骨形态发生蛋白-2（BMP-2），以及它们对骨折组织愈合和强度的有益影响。我们还发现，移植的表达胰岛素样生长因子-I（IGF-I）的MSC在骨折骨痂内分化成骨细胞，并通过诱导比单独的MSC更多的新骨形成来促进骨折愈合。该建议的中心假设是MSC通过自分泌和旁分泌作用促进再生微环境来改善骨折修复过程。具体而言，我们提出以下建议：具体目标1，以确定MSC是否通过诱导BMP-2表达改善骨折修复过程;具体目标2，以确定MSC编程表达IGF-I是否通过自分泌和旁分泌机制促进骨形成来改善骨折愈合。我们的研究结果将开辟新的视角，使MSC的再生能力得到充分的评价，从而在再生医学领域确立新的研究方向。一个综合的方法，结合在体内和体外研究基因工程小鼠，小鼠模型不愈合和新的方法来评估骨折愈合将被应用到实现拟议的目标。研究将具有重大的生物医学意义和影响，因为它们可以更好地理解MSC促进骨折修复的机制，这将为开发基于MSC的新疗法以促进骨不连患者的骨折愈合奠定基础。 公共卫生相关性：不愈合骨折仍然是一个具有挑战性的临床问题，在美国每年影响大约60万人。由于我们的老年人口越来越多，预期由于愈合不良和年龄相关的骨质疏松症恶化导致骨不连的发生率会增加。成人骨髓含有多能间充质基质细胞（MSC），具有成为治疗骨不连的新型治疗方法的所有特性。本提案的总体目标是了解MSC在骨折修复中发挥其有益作用的机制。阐明MSC如何能够对骨折再生线索做出反应并为组织再生提供足够的环境，将为开发新的基于MSC的治疗方法以治疗骨不连患者提供重要见解