Transplantation of side population cells restores the function of damaged exocrine glands through clusterin§

Authors

  • Kenji Mishima,

    1. Department of Pathology, Department of Pathology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Japan
    2. Department of Oral Pathology, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan
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  • Hiroko Inoue,

    1. Department of Pathology, Department of Pathology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Japan
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  • Tatsuaki Nishiyama,

    1. Department of Pathology, Department of Pathology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Japan
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  • Yo Mabuchi,

    1. Department of Physiology,Keio University School of Medicine, 35-Shinanomachi, Shinjuku-ku, Tokyo, Japan
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  • Yusuke Amano,

    1. Department of Pathology, Department of Pathology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Japan
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  • Fumio Ide,

    1. Department of Pathology, Department of Pathology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Japan
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  • Makoto Matsui,

    1. Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto, Japan
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  • Hiroyuki Yamada,

    1. First Department of Oral and Maxillofacial Surgery, and Department of Pathology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Japan
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  • Gou Yamamoto,

    1. Department of Oral Pathology, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan
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  • Junichi Tanaka,

    1. Department of Oral Pathology, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan
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  • Rika Yasuhara,

    1. Department of Oral Pathology, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan
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  • Takashi Sakurai,

    1. Department of Radiology and Division of Pharmacology and ESR Laboratories, Kanagawa Dental College, 82-Inaoka, Yokosuka, Japan
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  • Masaichi-Chang-il Lee,

    1. Department of Clinical Care Medicine, Division of Pharmacology and ESR Laboratories, Kanagawa Dental College, 82-Inaoka, Yokosuka, Japan
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  • Kan Chiba,

    1. Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
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  • Hidetoshi Sumimoto,

    1. Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan
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  • Yutaka Kawakami,

    1. Division of Cellular Signaling, Institute for Advanced Medical Research, and Keio University School of Medicine, 35-Shinanomachi, Shinjuku-ku, Tokyo, Japan
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  • Yumi Matsuzaki,

    1. Department of Physiology,Keio University School of Medicine, 35-Shinanomachi, Shinjuku-ku, Tokyo, Japan
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  • Kazuo Tsubota,

    1. Department of Ophthalmology, Keio University School of Medicine, 35-Shinanomachi, Shinjuku-ku, Tokyo, Japan
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  • Ichiro Saito

    Corresponding author
    1. Institute for Research and Education of Preemptive Medicine (iREP), Department of Pathology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Japan
    • Institute for Research and Education of Preemptive Medicine (iREP), Department of Pathology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Japan

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    • Telephone: 81-580-8360; Fax: 81-45-572-2888


  • Author contributions: K.M. and I.S.: conception and design, Collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; H.I., T.N., Y.M., Y.A., F.I., M.M., H.Y., G.Y., J.T., R.Y., T.S., M.-C.-i.L., K.C., and H.S.: collection and assembly of data and final approval of manuscript; Y.K. and K.T.: data analysis and interpretation and final approval of manuscript; Y.M.: collection and assembly of data, data analysis and interpretation, and final approval of manuscript.

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

  • §

    First published online in STEM CELLSEXPRESS July 10, 2012.

Abstract

Stem cell-based therapy has been proposed as a promising strategy for regenerating tissues lost through incurable diseases. Side population (SP) cells have been identified as putative stem cells in various organs. To examine therapeutic potential of SP cells in hypofunction of exocrine glands, SP cells isolated from mouse exocrine glands, namely, lacrimal and salivary glands, were transplanted into mice with irradiation-induced hypofunction of the respective glands. The secretions from both glands in the recipient mice were restored within 2 months of transplantation, although the transplanted cells were only sparsely distributed and produced no outgrowths. Consistent with this, most SP cells were shown to be CD31-positive endothelial-like cells. In addition, we clarified that endothelial cell-derived clusterin, a secretory protein, was an essential factor for SP cell-mediated recovery of the hypofunctioning glands because SP cells isolated from salivary glands of clusterin-deficient mice had no therapeutic potential, whereas lentiviral transduction of clusterin restored the hypofunction. In vitro and in vivo studies showed that clusterin had an ability to directly inhibit oxidative stress and oxidative stress-induced cell damage. Thus, endothelial cell-derived clusterin possibly inhibit oxidative stress-induced hypofunction of these glands. Stem Cells2012;30:1925–1937

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