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

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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.