The role of hyaluronic acid, CD44 and osteopontin in haemopoietic stem cell biology

骨髓和微环境细胞(MC)的相互作用在骨髓(BM)细胞的定位和调节中起着核心作用。具体地说，原始血细胞(HSC)的调节受它们的位置和它们表达的广泛的细胞黏附分子的影响。该项目基于申请者实验室的独特观察，表明三个分子透明质酸(HA)、CD44和骨桥蛋白在移植后HSC在骨髓中的定位以及调节其发育为成熟血细胞方面发挥关键作用。高度特定的局部相互作用调节血细胞的概念被概括为“生态位”假说，在这个假说中，MC形成一个特定的“生态位”。目前无法在原位识别HSC，因此无法分析它们的分布或调节这一过程的分子。间接证据表明，与骨骼密切相关的HSC‘壁龛’的存在。使用一种基于骨髓移植的新方法来跟踪细胞在骨髓中的寄存，我们第一次报道了移植的HSC的寄存不是一个随机的过程，而是导致供者来源的细胞迁移到骨髓界面。HSC上HA和CD44的存在以及骨髓微环境中CD44和骨桥蛋白的存在对这种倒伏模式是至关重要的。此外，我们现在有证据表明，HA和骨桥蛋白在维持HSC的原始状态中起着重要作用。这项建议旨在确认这三个分子在HSC生物学中的关键作用和相互作用。

Marrow and microenvironmental cell (MC) interactions play a central role in bone marrow (BM) cell localisation and regulation. Specifically, the regulation of primitive blood cells (HSC) is affected by their locality and their expression of a wide repertoire of cell adhesion molecules. This project is based upon the unique observations made in the applicants laboratory demonstrating that the three molecules hyaluronic acid (HA), CD44 and osteopontin play key roles in the localisation of HSC within the BM following transplantation and in regulating their development into mature blood cells. Encapsulating the concept of highly specific, local interactions regulating blood cells is the 'niche' hypothesis in which MC form a specific 'niche'. The current inability to identify HSC in situ makes it impossible to analyse either their distribution or molecules that regulate this process. Circumstantial evidence suggests the presence of HSC 'niches' in close association with the bone. Using a novel approach based on BM transplantation to track cells lodging in the BM, we were the first to report that the lodgement of a transplanted HSC is not a random process, but results in cells of donor origin migrating to the bone-marrow interface. The presence of HA and CD44 on the HSC and CD44 and ostepontin in the marrow microenvironment are critical for this pattern of lodgement. In addition, we now have evidence that HA and osteopontin are important in the maintenance of HSC in their primitive state. This proposal aims to confirm the critical roles and interactions of these three molecules in HSC biology.