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Human neural stem/progenitor cells, expanded in long-term neurosphere culture, promote functional recovery after focal ischemia in Mongolian gerbils

Authors

  • Satoru Ishibashi,

    1. Department of Neurology and Neurological Science, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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  • Masanori Sakaguchi,

    1. Department of Physiology, Keio University School of Medicine, Tokyo, Japan
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  • Toshihiko Kuroiwa,

    1. Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
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  • Mami Yamasaki,

    1. Institute for Clinical Research, Osaka National Hospital, Osaka, Japan
    2. Department of Neurosurgery, Osaka National Hospital, Osaka, Japan
    3. Tissue Engineering Research Center, National Institute of Advanced Industrial Science and Technology, Hyogo, Japan
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  • Yonehiro Kanemura,

    1. Institute for Clinical Research, Osaka National Hospital, Osaka, Japan
    2. Tissue Engineering Research Center, National Institute of Advanced Industrial Science and Technology, Hyogo, Japan
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  • Ichinose Shizuko,

    1. Instrumental Analysis Research Center, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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  • Takuya Shimazaki,

    1. Department of Physiology, Keio University School of Medicine, Tokyo, Japan
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  • Masafumi Onodera,

    1. Department of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan
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  • Hideyuki Okano,

    1. Department of Physiology, Keio University School of Medicine, Tokyo, Japan
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  • Hidehiro Mizusawa

    Corresponding author
    1. Department of Neurology and Neurological Science, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
    • Department of Neurology and Neurological Science, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
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Abstract

Transplantation of human neural stem cells (NSCs) is a promising potential therapy for neurologic dysfunctions after the hyperacute stage of stroke in humans, but large amounts of human NSCs must be expanded in long-term culture for such therapy. To determine their possible therapeutic potential for human stroke, human fetal neural stem/progenitor cells (NSPCs) (i.e., neurosphere-forming cells) were isolated originally from forebrain tissues of one human fetus, and expanded in long-term neurosphere culture (exceeding 24 weeks), then xenografted into the lesioned areas in the brains of Mongolian gerbils 4 days after focal ischemia. Sensorimotor and cognitive functions were evaluated during the 4 weeks after transplantation. The total infarction volume in the NSPC-grafted animals was significantly lower than that in controls. Approximately 8% of the grafted NSPCs survived, mainly in areas of selective neuronal death, and were costained with antibodies against neuronal nuclei antibody (NeuN), microtubule associated protein (MAP-2), glial fibrillary acidic protein (GFAP), and anti-2′3′ cyclic nucleotide 3′-phosphodiesterase (CNPase). Synaptic structures between NSPCs-derived neurons and host neurons were observed. Furthermore, gradual improvement of neurologic functions was observed clearly in the NSPC-grafted animals, compared to that in controls. Human NSPCs, even from long-term culture, remarkably improved neurologic functions after focal ischemia in the Mongolian gerbil, and maintained their abilities to migrate around the infarction, differentiate into mature neurons, and form synapses with host neuronal circuits. These results indicate that in vitro-expanded human neurosphere cells are a potential source for transplantable material for treatment of stroke. © 2004 Wiley-Liss, Inc.

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