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J. Biol. Chem., Vol. 278, Issue 37, 35491-35500, September 12, 2003

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Stem Cell-derived Neural Stem/Progenitor Cell Supporting Factor Is an Autocrine/Paracrine Survival Factor for Adult Neural Stem/Progenitor Cells^*

Hiroki Toda   ¶, Masayuki Tsuji , Ichiro Nakano , Kazuhiro Kobuke , Takeshi Hayashi ¶, Hironori Kasahara , Jun Takahashi , Akira Mizoguchi ||, Takeshi Houtani **, Tetsuo Sugimoto **, Nobuo Hashimoto , Theo D. Palmer ¶, Tasuku Honjo  and Kei Tashiro  

From the Department of Medical Chemistry, Kyoto University Graduate School of Medicine, Yoshida Konoe-cho, Sakyoku, Kyoto 606-8501, Japan, the Department of Neurosurgery, Kyoto University Graduate School of Medicine, Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan, the ^||Department of Anatomy, Mie University, School of Medicine, Tsucity, Mie 514-8507, Japan, the ^**Department of Anatomy and Brain Science, Kansai Medical University, Osaka 570-8506, Japan, the ^¶Department of Neurosurgery, Stanford University, Stanford, California 94305, and the Center for Molecular Biology and Genetics, Kyoto University Graduate School of Medicine, Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan

Recent evidence suggests that adult neural stem/progenitor cells (ANSCs) secrete autocrine/paracrine factors and that these intrinsic factors are involved in the maintenance of adult neurogenesis. We identified a novel secretory molecule, stem cell-derived neural stem/progenitor cell supporting factor (SDNSF), from adult hippocampal neural stem/progenitor cells by using the signal sequence trap method. The expression of SDNSF in adult central nervous system was localized to hippocampus including dentate gyrus, where the neurogenesis persists throughout life. In induced neurogenesis status seen in ischemically treated hippocampus, the expression of SDNSF was up-regulated. As functional aspects, SDNSF protein provided a dose-dependent survival effect for ANSC following basic fibroblast growth factor 2 (FGF-2) withdrawal. ANSCs treated by SDNSF also retain self-renewal potential and multipotency in the absence of FGF-2. However, SDNSF did not have mitogenic activity, nor was it a cofactor that promoted the mitogenic effects of FGF-2. These data suggested an important role of SDNSF as an autocrine/paracrine factor in maintaining stem cell potential and lifelong neurogenesis in adult central nervous system.

Received for publication, May 21, 2003

^* This work was supported in part by grants from the Ministry of Education, Culture, Sport, Science and Technology (to K. T.), by grants from Ministry of Health, Labor and Welfare (to K. T.), by Special Coordination Funds for Promoting Science and Technology (to J. T.), by Grants-in-Aid for Encouragement of Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to J. T.), and by funds from the Uehara Memorial Foundation (to H. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-75-751-4192; Fax: 81-75-751-4190; E-mail: ktashiro{at}mfour.med.kyoto-u.ac.jp.

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