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

将Notch基因胞浆区导入骨髓基质细胞，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。目前的方法大多数细胞分化为神经元，很少形成神经胶质细胞。电生理学上，这些神经元表现为神经元表型，并显示出功能。在GDNF和其他细胞因子的进一步刺激下，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氏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。骨髓基质细胞被证明具有另一种分化能力。当骨髓基质细胞的克隆用肿瘤促进剂TPA处理时，它们变成了多核巨细胞。该细胞具有破骨细胞的标志，如耐酒石酸酸性磷酸酶，这是一种罕见的骨髓基质细胞被诱导分化为造血系细胞的现象。由于有一种假设，即骨髓基质细胞通过与移植区分化的细胞融合而显示出多潜能，我们测试了细胞融合的可能性。当将CFP或GFP等标记基因导入细胞，并将具有不同标记的细胞混合在一起并用TPA刺激时，出现了具有多个标记的细胞，表明细胞融合有助于多核细胞的出现，但不排除内丝分裂(细胞分裂而不是核分裂)的可能性。已知破骨细胞通过RANK/RANKL或M-CSF/c-FMS信号转导途径的作用而发展，但在目前的病例中，这些途径都没有发挥作用，这表明可能有新的途径起作用。

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.