Xenotransplanted Embryonic Kidney Provides a Niche for Endogenous Mesenchymal Stem Cell Differentiation into Erythropoietin-Producing Tissue

Authors

  • Kei Matsumoto,

    1. Project Laboratory for Kidney Regeneration, Institute of DNA Medicine,The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
    2. Department Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
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  • Takashi Yokoo,

    Corresponding author
    1. Project Laboratory for Kidney Regeneration, Institute of DNA Medicine,The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
    2. Department Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
    3. Meiji University International Institute for Bio-Resource Research, Kawasaki, Kanagawa, Japan
    • Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan
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    • Telephone: +81-3-3433-1111; Fax: +81-3-3433-4297

  • Hitomi Matsunari,

    1. Meiji University International Institute for Bio-Resource Research, Kawasaki, Kanagawa, Japan
    2. Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Kanagawa, Japan
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  • Satomi Iwai,

    1. Meiji University International Institute for Bio-Resource Research, Kawasaki, Kanagawa, Japan
    2. Department of Surgery (I), Kitasato University School of Veterinary Medicine, Towada, Aomori, Japan
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  • Shinya Yokote,

    1. Project Laboratory for Kidney Regeneration, Institute of DNA Medicine,The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
    2. Department Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
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  • Takumi Teratani,

    1. Division of Development of Advanced Treatment, Center for Development of Advanced Medical Technology, Jichi Medical University, Shimotsuke-shi, Tochigi-ken, Japan
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  • Yousof Gheisari,

    1. Project Laboratory for Kidney Regeneration, Institute of DNA Medicine,The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
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  • Osahiko Tsuji,

    1. Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
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  • Hideyuki Okano,

    1. Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
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  • Yasunori Utsunomiya,

    1. Department Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
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  • Tatsuo Hosoya,

    1. Department Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
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  • Hirotaka James Okano,

    1. Project Laboratory for Kidney Regeneration, Institute of DNA Medicine,The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
    2. Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
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  • Hiroshi Nagashima,

    1. Meiji University International Institute for Bio-Resource Research, Kawasaki, Kanagawa, Japan
    2. Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Kanagawa, Japan
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  • Eiji Kobayashi

    1. Meiji University International Institute for Bio-Resource Research, Kawasaki, Kanagawa, Japan
    2. Division of Development of Advanced Treatment, Center for Development of Advanced Medical Technology, Jichi Medical University, Shimotsuke-shi, Tochigi-ken, Japan
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  • Author contributions: K.M., S.Y., and Y.G.: performed transgenic mice and rat experiments and contributed to manuscript preparation; T.Y.: planned and supervised all experiments and contributed to manuscript preparation; H.M. and H.N.: performed pig embryo experiments and contributed to manuscript preparation; S.I.: performed surgical procedures on cats and contributed to manuscript preparation; T.T.: performed isolation and establishment of mesenchymal stem cells and contributed to manuscript preparation; O.T., J.O., and H.O.: established the E2F1 mouse and contributed to manuscript preparation; Y.U. and T.H.: provided administrative, technical and material support, and contributed to manuscript preparation; E.K.: had full access to all study data, takes responsibility for the integrity of data and the accuracy of data analysis, and contributed to manuscript preparation.

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

  • First published online in STEM CELLSEXPRESS April 4, 2012.

Abstract

Recent findings have demonstrated that stem cells can differentiate into mature tissue when supplied with a niche containing factors identical to those in the normal developmental program. A niche for the development of an organ can be provided by xenotransplantation of a similar developing organ. However, this process has many technical, safety, and ethical concerns. Here, we established xenotransplantation models that control endogenous mesenchymal stem cell (MSC) differentiation into mature erythropoietin (EPO)-producing tissue in a niche provided by a developing xenometanephros. Transplantation of rat metanephroi into mouse omentum, and similarly pig metanephroi into cat omentum, led to the recruitment of host cells and EPO production. EPO-expressing cells were not differentiated from integrating vessels because they did not coexpress endothelial markers (Tie-2 and VE-cadherin). Instead, EPO-expressing cells were shown to be derived from circulating host cells, as shown by enhanced green fluorescent protein (EGFP) expression in the grown transplants of chimeric mice bearing bone marrow from a transgenic mouse expressing EGFP under the control of the EPO promoter. These results suggest that donor cell recruitment and differentiation in a xenotransplanted developing organ may be consistent between species. The cells responsible for EPO expression were identified as MSCs by injecting human bone marrow-derived MSCs and endothelial progenitor cells into NOD/SCID mice. Furthermore, using metanephroi from transgenic ER-E2F1 suicide-inducible mice, the xenotissue component could be eliminated, leaving autologous EPO-producing tissue. Our findings may alleviate adverse effects due to long-lasting immunosuppression and help mitigate ethical concerns. STEM CELLS2012;30:1228–1235

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