Specific induction of functional neurons and skeletal muscle cells from bone marrow stromal cells and their application for auto-cell transplantation therapy in neuro-and muscle degenerative diseases

骨髓基质细胞（MSCs）具有在特定条件下分化为各种细胞类型的能力，如骨细胞、软骨细胞和脂肪细胞。在这里，我们展示了一个高效和特异性的诱导雪旺细胞（周围胶质细胞），神经元和骨骼肌细胞从大鼠和人间充质干细胞。通过NICD转染，再用bFGF+ CNTF + forskolin给予营养因子，可以实现神经元诱导。转染NICD后，MSCs表达与神经干细胞和神经祖细胞相关的标志物，随后给予营养因子诱导有丝分裂后神经元，而不分化胶质细胞。部分诱导细胞的动作电位与功能神经元的特征相符。用GDNF进一步处理神经元增加了多巴胺产生细胞的比例，这些神经元移植在帕金森病大鼠模型中显示出改善。高效的骨骼肌诱导也可以通过结合细胞因子和NICD转染来实现。诱导细胞移植到退行性肌肉后分化成肌纤维。由于诱导细胞含有卫星样细胞，它们有助于在重复损伤后的后续再生，而无需额外的细胞移植。由于我们的诱导系统不依赖于罕见的干细胞群，而是可以利用易于分离和扩增的普通MSCs群，因此可以在治疗规模上获得功能性的雪旺细胞，神经元和骨骼肌细胞。我们的MSC分化系统可能会对神经退行性和肌肉退行性疾病的最终细胞治疗做出重大贡献。

Bone marrow stromal cells (MSCs) have the capability under specific conditions to differentiate into various cell types, such as osteocytes, chondrocytes and adipocytes. Here we demonstrate a highly efficient and specific induction of Schwann cells (peripheral glial cells), neurons and skeletal muscle cells from both rat and human MSCs.Neuronal induction could be achieved by NICD transfection followed by trophic factor administration of bFGF+ CNTF + forskolin. MSCs expressed markers related to neural stem cell and neuronal progenitor cells after transfection with NICD, and subsequent administration of trophic factors induced post-mitotic neurons without differentiation of glial cells. Some of induced cells showed action potentials compatible with characteristics of functional neurons. Further treatment of the neurons with GDNF increased the proportion of dopamine-producing cells and transplantation of these neurons showed improvement in rat model of Parkinson's disease. Highly efficient skeletal muscle induction could also be achieved by the administration of a combination of cytokines followed by NICD transfection. Induced cells differentiate into muscle fibers upon transplantation into degenerated muscles. Since induced cells contained satellite-like cells, they contributed to subsequent regeneration upon repetitive damage without additional transplantation of cells.Since our induction system does not depend on a rare stem cell population, but can utilize the general population of MSCs which can be easily isolated and expanded, functional Schwann cells, neurons and skeletal muscle cells can be obtained on a therapeutic scale. Our MSC differentiation system may contribute substantially to a major advance toward eventual cell-based therapies for neurodegenerative and muscle degenerative diseases.