Brain from bone: Efficient “meta-differentiation” of marrow stroma-derived mature osteoblasts to neurons with Noggin or a demethylating agent

Authors

  • J. Kohyama,

    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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  • 1 H. Abe,

    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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  • 1 T. Shimazaki,

    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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  • 2 A. Koizumi,

    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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  • 2 H. Okano,

    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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  • 2 J. Hata,

    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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  • 1 A. Umezawa,

    Corresponding author
    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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  • 1 () T. Shimazaki,

    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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  • 3 H. Okano,

    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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  • 3 K. Nakashima,

    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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  • 4 T. Taga,

    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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  • and 4 S. Gojo 5

    1. 1 Department of Pathology and 2Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
      Tel: + 81 3 5363 3764, Fax: + 81 3 3353 3290
      3Division of Neuroanatomy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan4Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1, Honjo, Kumamoto 860-0811, Japan5Department of Cardiac Surgery, Saitama Medical Center, Kawagoe, Japan
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✉ e-mail: umezawa@1985.jukuin.keio.ac.jp

Abstract

Abstract Bone marrow stromal cells are able to differentiate into adipogenic, chondrogenic, myogenic, osteogenic, and cardiomyogenic lineages, all of which are limited to a mesoderm-derived origin. In this study, we showed that neurons, which are of an ectoderm-origin, could be generated from marrow-derived stromal cells by specific inducers, fibronectin/ornithine coating, and neurosphere formation. The neurons generated from marrow stroma formed neurites, expressed neuron-specific markers and genes, and started to respond to depolarizing stimuli as functional mature neurons. Among stromal cells, isolated mature osteoblasts which had strong in vivo osteogenic activity could be efficiently converted into functional neurons. This transdifferentiation or meta-differentiation was enhanced by Noggin, an inhibitor of bone morphogenetic proteins, in comparison with 5-azacytidine, a demethylating agent capable of altering the gene expression pattern. Marrow stroma is therefore a potential source of cells for neural cell transplantation.

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