Neuropilin-1调控脑胶质瘤中相关间充质干细胞分化及参与血管拟态构成机制的研究

As an essential component in vessels, pericytes take an important role in tumor angiogenesis process.Thus, pericytes could be an promising target for tumor anti-angiogenesis treatment. For the first time, glioblastoma-dervied mesenchymal stem cells (gbMSCs) were isolated from fresh tumor tissues obtained from glioblastoma patients.Moreover, a differentiation model which gbMSCs could be induced into pericytes in glioblastoma microenvironment was established. Meanwhile, the increased expression of neuropilin-1 was observed in this model...So in the current study, the differertiation model which gbMSCs were induced into pericytes will be established in vitro and in vivo. the following experiments will be investigated: .1.the expression of neuropilin-1 in the differentiation and angiogenesis processes of pericytes;.2.the relation between the neuropilin-1 expression and the ability of differentiation and angiogenesis in pericytes;.3.the upstream factors which can affect the expression of neuropilin-1 and the differentiation and angiogenesis abilities in pericytes; .4.the downstream pathway which neuropilin-1 regulate the differentiation and angiogenesis abilities in pericytes;.5.the reaction of anti-angiogenesis therapy aim to neuropilin-1...so the mechanism of neuropilin-1 regulate the differentiation and angiogenesis processeS of glioblastoma associated mesenchymal stem cells will be analysised. the current study is expected to find new celltype or molecule target for human glioblastoma anti-angiogenesis therapy.

血管周细胞参与肿瘤血管拟态构成并起重要作用，可能成为抗肿瘤血管治疗新的靶点。课题申请人从脑胶质瘤患者组织中成功分离出胶质瘤相关间充质干细胞（glioblastoma-derived mesenchymal stem cell，gbMSC），并建立了脑胶质瘤微环境下gbMSC分化的细胞模型，分化后的细胞表达血管周细胞标记物和血管成形功能。同时观察在该分化过程中neuropilin-1的增高表达。本课题拟建立脑胶质瘤中相关间充质干细胞分化的体内外模型，观察neuropilin-1的表达和改变对其分化和参与血管拟态构成的影响，观察影响neuropilin-1表达的上游因子和下游信号通路，从而探讨neuropilin-1调控脑胶质瘤微环境下相关间充质干细胞分化和参与血管拟态构成的分子机制。本课题的实施可能为脑胶质瘤的抗肿瘤血管治疗提供新的靶细胞和分子靶点。

肿瘤血管的形成和维持在胶质母细胞瘤的发展中起关键作用。从原发性人类胶质母细胞瘤中分离了脑胶质瘤相关间充质干细胞（gb-MSC），证明了gb-MSC向周细胞的转化，表明gb-MSC衍生的周细胞能够在新血管组装过程中形成血管结构并粘附于内皮细胞，在神经胶质瘤微环境中促进新血管形成。此外，由胶质母细胞瘤衍生的间充质干细胞由CD90低表达gb-MSC和CD90高表达gb-MSC组成，是在神经胶质瘤血管形成中更具活性的gb-MSC的亚群。因此，研究两种亚群的生物学特性及其功能具有重要意义。通过分离两种亚群细胞来探讨其在肿瘤进展中的作用及其机制，研究发现，CD90高表达的细胞主要通过增加增殖、迁移和粘附来促进胶质瘤进展，而CD90低表达的细胞主要通过向周细胞分化和刺激内皮细胞血管形成来促进胶质瘤进展。CD90高表达条件培养液中SDF-1α、CCL5、MMP9的含量显著高于CD90低表达的，而CD90低表达条件培养液中VEGF、bFGF、IL-6的含量明显高于CD90高表达的。然而，要明确潜在的机制还需要更进一步探索。这些研究结果为未来治疗胶质瘤患者提供了新的靶点。