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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

骨髓基质细胞特异性诱导功能性神经元和骨骼肌细胞及其在神经和肌肉退行性疾病自体细胞移植治疗中的应用

基本信息

批准号：
17590161
负责人：
MORI Dezawa
金额：
$ 2.3万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

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.

骨髓基质细胞（MSC）在特定条件下具有分化成各种细胞类型的能力，例如骨细胞、软骨细胞和脂肪细胞。在这里，我们展示了对来自大鼠和人类 MSC 的雪旺细胞（外周胶质细胞）、神经元和骨骼肌细胞的高效和特异性诱导。神经元诱导可以通过 NICD 转染然后给予 bFGF+ CNTF + 毛喉素的营养因子来实现。 NICD转染后，MSCs表达与神经干细胞和神经元祖细胞相关的标志物，随后施用营养因子诱导有丝分裂后神经元，但没有神经胶质细胞的分化。一些诱导细胞表现出与功能神经元特征相一致的动作电位。用GDNF进一步治疗神经元增加了产生多巴胺的细胞的比例，并且这些神经元的移植在帕金森病的大鼠模型中显示出改善。通过施用细胞因子组合，然后进行 NICD 转染，也可以实现高效的骨骼肌诱导。诱导细胞在移植到退化肌肉中后分化成肌纤维。由于诱导细胞含有卫星样细胞，它们有助于重复损伤后的再生，而无需额外移植细胞。由于我们的诱导系统不依赖于稀有干细胞群，而是可以利用易于分离和扩增的普通间充质干细胞群，因此可以在治疗规模上获得功能性雪旺细胞、神经元和骨骼肌细胞。我们的间充质干细胞分化系统可能会对最终基于细胞的神经退行性疾病和肌肉退行性疾病疗法的重大进展做出重大贡献。