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The mechanism of the induction of differentiation of bone marrow stromal stem cells and its application

骨髓基质干细胞诱导分化的机制及其应用

基本信息

批准号：
14370008
负责人：
SAWADA Hajime
金额：
$ 7.04万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

By transfection of the cytoplasmic domain of Notch gene and stimulation by cytokines such as basic FGF, bone marrow stromal cells differentiated into neurons. By the present method most of the cells differentiated into neurons and few glial cells were formed. Electrophysiologically these neurons exhibit neuronal phenotype and shown to be functioning. Further stimulation of these cells by GDNF and other cytokines, these neurons restrict their developmental direction to dopaminergic neurons. When these cells were transplanted into the brain of model rats for Parkinson's disease, their symptoms were alleviated. These results seemed to open the way for the clinical treatment of Parkinson's disease.The bone marrow stromal cells were shown to have another repertoire of differentiation. When a clone from bone marrow stromal cells were treated with a tumor promoter TPA, they changed to multinuclear giant cells. The cells exhibit markers of osteoclasts such as tartrate-resistant acid phosphatase, and this case is a rare phenomenon that bone marrow stromal cells were induced to differentiate into cells of hematopoietic lineage. Since there is a hypothesis that bone marrow stromal cells exhibit multipotentiality by fusing with differentiated cells in the transplanted area, we tested the possibility of cell fusion. When marker genes such as CFP or GFP were introduced in to the cells and the cells with distinct markers were mixed and stimulated by TPA, cells with multiple markers appeared indicating that the cell fusion contributes to the appearance of multinuclear cells, although the possibility of endomitosis (cell division without nuclear division) cannot be excluded. Osteoclasts are known to develop through the action of RANK/RANKLor M-CSF/c-fms signal transductions, but in the present case none of these pathways was shown to be working indicating a possibility of contribution of new pathways.

通过转染Notch基因胞浆区，并在碱性成纤维细胞生长因子等细胞因子的刺激下，骨髓基质细胞分化为神经元。用本方法培养的大部分细胞分化为神经元，少数形成胶质细胞。在电生理学上，这些神经元表现出神经元表型并显示出功能。GDNF和其他细胞因子进一步刺激这些细胞，这些神经元将其发育方向限制为多巴胺能神经元。当这些细胞被移植到帕金森病模型大鼠的大脑中时，它们的症状得到了缓解。这些结果似乎为帕金森病的临床治疗开辟了道路。骨髓基质细胞显示出另一种分化能力。当用肿瘤促进剂TPA处理来自骨髓基质细胞的克隆时，它们变成多核巨细胞。这些细胞表现出破骨细胞的标志物，例如抗酒石酸酸性磷酸酶，这种情况是骨髓基质细胞被诱导分化为造血谱系细胞的罕见现象。由于存在骨髓基质细胞通过与移植区域中的分化细胞融合而表现出多潜能性的假设，我们测试了细胞融合的可能性。当将标记基因如CFP或GFP引入细胞中，并将具有不同标记的细胞混合并用TPA刺激时，出现具有多种标记的细胞，表明细胞融合有助于多核细胞的出现，尽管不能排除内有丝分裂（细胞分裂而无核分裂）的可能性。已知破骨细胞通过RANK/RANKL或M-CSF/c-fms信号转导作用发育，但在本例中，这些途径均未显示起作用，表明可能存在新途径。