Subventricular Zone-Derived Oligodendrogenesis in Injured Neonatal White Matter in Mice Enhanced by a Nonerythropoietic Erythropoietin Derivative§

Authors

  • Eisuke Kako,

    1. Department of Developmental and Regenerative BiologyNagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
    2. Department of Anesthesiology and Medical Crisis ManagementNagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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  • Naoko Kaneko,

    1. Department of Developmental and Regenerative BiologyNagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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  • Mineyoshi Aoyama,

    1. Department of Molecular NeurobiologyNagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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  • Hideki Hida,

    1. Department of Neurophysiology and Brain ScienceNagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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  • Hirohide Takebayashi,

    1. Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Aichi, Japan
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  • Kazuhiro Ikenaka,

    1. Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Aichi, Japan
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  • Kiyofumi Asai,

    1. Department of Molecular NeurobiologyNagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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  • Hajime Togari,

    1. Department of Neonatology and Pediatrics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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  • Kazuya Sobue,

    1. Department of Anesthesiology and Medical Crisis ManagementNagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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  • Kazunobu Sawamoto

    Corresponding author
    1. Department of Developmental and Regenerative BiologyNagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
    • Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan

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    • Telephone: +81-52-853-8532; Fax: +81-52-851-1898


  • Author contributions: E.K. and N.K.: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing; M.A.: conception and design and collection and assembly of data; H.H., K.A., H. Togari: conception and design; H. Takebayashi: provision of study material; K.I.: provision of study material; K. Sobue: conception and design and administrative support; K. Sawamoto: conception and design, financial support, data analysis and interpretation, and manuscript writing.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS August 13, 2012.

Abstract

Perinatal hypoxia-ischemia (HI) frequently causes white-matter injury, leading to severe neurological deficits and mortality, and only limited therapeutic options exist. The white matter of animal models and human patients with HI-induced brain injury contains increased numbers of oligodendrocyte progenitor cells (OPCs). However, the origin and fates of these OPCs and their potential to repair injured white matter remain unclear. Here, using cell-type- and region-specific genetic labeling methods in a mouse HI model, we characterized the Olig2-expressing OPCs. We found that after HI, Olig2+ cells increased in the posterior part of the subventricular zone (pSVZ) and migrated into the injured white matter. However, their oligodendrocytic differentiation efficiency was severely compromised compared with the OPCs in normal tissue, indicating the need for an intervention to promote their differentiation. Erythropoietin (EPO) treatment is a promising candidate, but it has detrimental effects that preclude its clinical use for brain injury. We found that long-term postinjury treatment with a nonerythropoietic derivative of EPO, asialo-erythropoietin, promoted the maturation of pSVZ-derived OPCs and the recovery of neurological function, without affecting hematopoiesis. These results demonstrate the limitation and potential of endogenous OPCs in the pSVZ as a therapeutic target for treating neonatal white-matter injury. STEM Cells2012;30:2234–2247

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