TGF-BETA AND IGF IN MESENCHYMAL STEM CELL CHONDROGENESIS

用于骨折修复的骨再生依赖于招募的软骨-骨祖细胞的数量 骨折部位。据报道，在620万人中，有10%的人骨折愈合过程受到损害 骨折在美国每年都会发生，导致严重的发病率和死亡率。限制 干细胞数量的减少以及合成和分解代谢激素与生长因子之间的失衡是关键 确定骨折修复失败的要素。在修复过程中软骨模板的形成是必不可少的 骨折修复过程。成人骨髓含有间充质干细胞(MSC) 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从自我复制过程转化为软骨细胞分化过程的机制尚不清楚。 我们的长期目标是了解决定再生能力的分子机制 骨髓间充质干细胞有潜力设计更有效的治疗方法来改善骨折愈合过程。我们的研究 证明转化生长因子-β和胰岛素样生长因子-L 通过诱导软骨前体细胞凝集、生长和分化来确定MSC的软骨形成潜能 分化为软骨细胞。我们还证明，当系统地输注MSC时， 专门被招募到骨折部位，在那里分化为软骨细胞。我们假设 转化生长因子-β和胰岛素样生长因子-I在软骨形成过程中具有合成代谢诱导作用 MSC.我们进一步假设，转化生长因子-β和胰岛素样生长因子-I的软骨诱导作用可用于 工程师MSC促进骨折愈合过程。这项建议的两个具体目标是：1) 发现转化生长因子-β和胰岛素样生长因子-I决定间充质干细胞软骨形成潜能的机制；2) 确定转化生长因子-β和胰岛素样生长因子-I在骨髓间充质干细胞骨折修复能力中的作用。要实现这些目标 具体目标，提案将结合结构生物学、生物化学、小鼠模型和分子成像 体内示踪间充质干细胞的技术。我们期待这一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多了解。理解 转化生长因子-β和胰岛素样生长因子-I在骨髓间充质干细胞成软骨潜能中的作用 基于间充质干细胞的转化生长因子-β和胰岛素样生长因子-I体外递送系统的研制 骨折愈合。

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.