Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growth-associated protein-43-positive fibers after rat spinal cord injury

Authors

  • Takeshi Ikegami,

    1. Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
    2. Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
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  • Masaya Nakamura,

    1. Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
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  • Junichi Yamane,

    1. Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
    2. Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
    3. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan
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  • Hiroyuki Katoh,

    1. Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
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  • Seiji Okada,

    1. Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
    2. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan
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  • Akio Iwanami,

    1. Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
    2. Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
    3. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan
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  • Kota Watanabe,

    1. Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
    2. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan
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  • Ken Ishii,

    1. Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
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  • Fumikazu Kato,

    1. Central Research Laboratories, Seikagaku Corporation, Tokyo, Japan
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  • Hiroshi Fujita,

    1. Glycoconjugate Research Center, Seikagaku Corporation, Kanagawa, Japan
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  • Toyomi Takahashi,

    1. Central Research Laboratories, Seikagaku Corporation, Tokyo, Japan
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  • Hirotaka James Okano,

    1. Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
    2. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan
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  • Yoshiaki Toyama,

    1. Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
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  • Hideyuki Okano

    1. Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan
    2. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan
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Dr Hideyuki Okano, 2Department of Physiology, as above.
E-mail: hidokano@sc.itc.keio.ac.jp

Abstract

We previously reported that the transplantation of neural stem/progenitor cells (NSPCs) can contribute to the repair of injured spinal cord in adult rats and monkeys. In some cases, however, most of the transplanted cells adhered to the cavity wall and failed to migrate and integrate into the host spinal cord. In this study we focused on chondroitin sulfate proteoglycan (CSPG), a known constituent of glial scars that is strongly expressed after spinal cord injury (SCI), as a putative inhibitor of NSPC migration in vivo. We hypothesized that the digestion of CSPG by chondroitinase ABC (C-ABC) might promote the migration of transplanted cells and neurite outgrowth after SCI. An in vitro study revealed that the migration of NSPC-derived cells was inhibited by CSPG and that this inhibitory effect was attenuated by C-ABC pre-treatment. Consistently, an in vivo study of C-ABC treatment combined with NSPC transplantation into injured spinal cord revealed that C-ABC pre-treatment promoted the migration of the transplanted cells, whereas CSPG-immunopositive scar tissue around the lesion cavity prevented their migration into the host spinal cord in the absence of C-ABC pre-treatment. Furthermore, this combined treatment significantly induced the outgrowth of a greater number of growth-associated protein-43-positive fibers at the lesion epicentre, compared with NSPC transplantation alone. These findings suggested that the application of C-ABC enhanced the benefits of NSPC transplantation for SCI by reducing the inhibitory effects of the glial scar, indicating that this combined treatment may be a promising strategy for the regeneration of injured spinal cord.

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