TGF-BETA AND IGF IN MESENCHYMAL STEM CELL CHONDROGENESIS

间充质干细胞软骨形成中的 TGF-β 和 IGF

• 批准号: 7989036
• 负责人: Anna Spagnoli
• 金额: $ 2.1万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989036
• 关键词: Adult; Animals; Apoptosis; Area; Biochemistry; Biological Assay; Biology; Bone Marrow; Bone callus; Cartilage; Cell Count; Cell Therapy; Cell physiology; Cells; Chondrocytes; Chondrogenesis; Collagen; Cues; Development; Differentiation and Growth; Engineering; Estrogens; Failure; Female; Fibrinogen; Fluorescence; Fracture; Fracture Healing; Gene Transfer; Genes; Genetic Markers; Goals; Growth; Growth Factor; Growth Factor Receptors; Healed; Hormones; Hypertrophy; Imaging Techniques; Impairment; In Vitro; Indium; Insulin; Lead; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Pathway interactions; Physical condensation; Play; Process; Recruitment Activity; Reporter; Reporting; Research; Role; Signal Pathway; Signal Transduction; Site; Somatomedins; Staging; Stem cells; System; Testing; Tibial Fractures; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Type I Insulin; United States; base; bone; cell growth; chemical genetics; effective therapy; gene therapy; healing; improved; in vivo; middle age; molecular imaging; mortality; mouse model; novel; null mutation; osteoprogenitor cell; progenitor; regenerative; repaired; response; structural biology; tibia; tissue regeneration

Regeneration of bone for fracture repair relies on the number of chondro-osteoprogenitors recruited to the fracture site. An impairment of the fracture healing process is reported in 10% of the 6.2 million fractures occurring annually in the United States, leading to significant morbidity and mortality. Limitation of stem cell number and imbalance between anabolic and catabolic hormones and growth factors are key elements in determining fracture repair failure. Formation of a cartilage template is essential during the fracture repair process. Adult bone marrow (BM) contains a reservoir of mesenchymal stem cells (MSC) with in vitro and in vivo potential of becoming cartilage. However, the molecular signals and growth factors that convert MSC from the process of self-replication to that of chondrogenic differentiation are unknown. Our long-term objective is to understand the molecular mechanisms that determine the regenerative potential of MSC to devise more effective therapies to ameliorate the fracture healing process. Our studies demonstrate that transforming growth factor beta (TGF-beta) and insulin-like growth factor-l (IGF-I) determine the chondrogenic potential of MSC by inducing chondroprogenitor condensation, growth and differentiation into chondrocytes. We have also demonstrated that MSC when systemically infused are specifically recruited to the fracture site where they differentiate into chondrocytes. We hypothesize that TGF-beta and IGF-I have anabolic chondroinductive effects in the cartilage formation process derived from MSC. We further hypothesize that the chondroinductive actions of TGF-beta and IGF-I can be used to engineer MSC to promote the fracture healing process. The two Specific Aims of this proposal are:1) to discover the mechanisms by which TGF-beta and IGF-I determine the MSC chondrogenic potential; 2) to determine the role of TGF-beta and IGF-I in the fracture repair capacity of MSC. To accomplish these specific aims, proposal will combine structural biology, biochemistry, mouse models and molecular imaging techniques for tracing MSC in vivo. We expect that the results of this multi-faceted experimental approach will provide greater understanding of the basic biology and regenerative capacity of MSC. Understanding the role of TGF-beta and IGF-I in the chondrogenic potential of MSC will provide critical information for the development of an ex-vivo MSC-based TGF-beta and IGF-I delivery system capable of potentiating fracture healing.

用于骨折修复的骨再生依赖于募集的软骨骨祖细胞的数量， 骨折部位据报道，在620万名患者中，有10%的人骨折愈合过程受损。 在美国每年发生的骨折，导致显著的发病率和死亡率。限制 干细胞数量和合成代谢和分解代谢激素和生长因子之间的不平衡是关键 确定骨折修复失败的要素。软骨模板的形成是必不可少的， 骨折修复过程成人骨髓（BM）含有间充质干细胞（MSC）的储库 在体外和体内都有成为软骨的潜力。然而，分子信号和生长因子 将MSC从自我复制的过程转化为软骨形成分化的过程是未知的。 我们的长期目标是了解决定再生的分子机制， MSC设计更有效的治疗方法来改善骨折愈合过程的潜力。我们的研究 证明转化生长因子β（TGF-β）和胰岛素样生长因子-1（IGF-I） 通过诱导软骨祖细胞凝聚、生长和增殖来确定MSC的软骨形成潜力， 分化成软骨细胞。我们还证明了全身输注MSC时， 专门募集到骨折部位，在那里它们分化成软骨细胞。我们假设 TGF-β和IGF-I在软骨形成过程中具有合成代谢软骨诱导作用， MSc.我们进一步假设TGF-β和IGF-I的软骨诱导作用可用于 工程MSC促进骨折愈合过程。这项建议的两个具体目标是：1） 发现TGF-β和IGF-I决定MSC软骨形成潜力的机制; 2） 确定TGF-β和IGF-I在MSC的骨折修复能力中的作用。完成这些 具体目标，提案将结合联合收割机结构生物学、生物化学、小鼠模型和分子成像 用于追踪体内MSC的技术。我们希望这种多方面的实验方法的结果 将提供对MSC的基本生物学和再生能力的更好理解。理解 TGF-β和IGF-I在MSC的软骨形成潜能中的作用将为MSC的软骨形成提供关键信息。 开发了一种离体的基于MSC的TGF-β和IGF-I递送系统， 骨折愈合