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Development of cell therapies using reversibly immortalized human pancreatic beta cell lines

Research Project

Project/Area Number 16390380
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionOkayama University

Principal Investigator

KOBAYASHI Naoya  Okayama University, University Hospital of Medicine and Dentistry, Assistant, 医学部・歯学部附属病院, 助手 (10325102)

Co-Investigator(Kenkyū-buntansha) IWAGAKI Hiromi  Okayama University, University Hospital of Medicine and Dentistry, Lecturer, 医学部・歯学部附属病院, 講師 (50240867)
KAGAWA Shunsuke  Okayama University, University Hospital of Medicine and Dentistry, Assistant, 医学部・歯学部附属病院, 助手 (00362971)
SHIRAKAWA Yasuhiro  Okayama University, University Hospital of Medicine and Dentistry, Medical Staff, 医学部・歯学部附属病院, 医員 (60379774)
MOCHITATE Katsumi  National institute for Environmental Studies, Environmental Health sciences Division, Senior Researcher, 環境健康研究領域, 上席研究員 (20132863)
MATSUKAWA Hiroyoshi  Medical School, Lecture, 医学部, 非常勤講師 (10379729)
藤原 俊義  岡山大学, 医学部・歯学部附属病院, 助教授 (00304303)
中路 修平  クラレメディカル株式会社, 新規事業開発部, 担当部長
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2005: ¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 2004: ¥7,800,000 (Direct Cost: ¥7,800,000)
Keywordslentiviral vector / human telomerase gene / insulin-secreting immortalized human cells / animal model of diabetes / international information exchange / Canada / ブタ糖尿病モデル
Research Abstract

After thawing the cryopreserved islets with UW solution, the islet cells showed an efficient monolayer formation and facilitated effective lentivirus-mediated transduction. Monolayer formation of mouse islets was efficiently achieved by the use of extracellular matrices derived from 804G cells. We successfully made a diabetes model in pigs to perform total pancreatectomy. Such diabetic pigs died of ketoacidosis within 10 days after surgery. The model would be useful to assess the efficacy of diabetes-targeted cell therapies. A human pancreatic beta cell line that is functionally equivalent to primary beta cells has not been available. We established a reversibly immortalized human beta cell clone (NAKT-15) by transfection of primary human beta cells with a retroviral vector containing simian virus 40 large T antigen (SV40T) and human telomerase reverse transcriptase (hTERT) cDNAs flanked by paired recombination target loxPs, which allows deletion of SV40T and hTERT genes by Cre recombinase. Reverted NAKT-15 cells expressed beta cell transcription factors (Isl-1,Pax 6,Nkx 6.1,Pdx-1), prohormone convertases 1/3 and 2, and secretory granule proteins, and secreted insulin in response to glucose, similar to normal human islets. Transplantation of NAKT-15 cells into streptozotocin-induced diabetic SCID mice resulted in perfect control of blood glucose within 2 weeks ; mice remained normoglycemic for longer than 30 weeks. The establishment of a beta cell line is one step toward the potential cure of diabetes by transplantation.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (14 results)

All 2005 2004

All Journal Article (14 results)

  • [Journal Article] 糖尿病を標的とした細胞療法に向けたインスリン分泌ヒト細胞株の作成.2005

    • Author(s)
      小林直哉
    • Journal Title

      今日の移殖 18(4)

      Pages: 429-434

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A human β-cell line for transplantation therapy to control type 1 diabetes.2005

    • Author(s)
      Michiki Narushima
    • Journal Title

      Nature Biotechnology 23(10)

      Pages: 1274-1282

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Establishment of insulin-secreting human cell lines for diabetes-targeted cell therapies.2005

    • Author(s)
      Kobayashi N, Okitsu T, Chen Y, Yamatsuji T, Shirakawa Y, Inai K, Akasu H, Tanaka N
    • Journal Title

      Transplantation Now 18(4)

      Pages: 429-434

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A human β-cell line for transplantation therapy to control type 1 diabetes.2005

    • Author(s)
      Narushima M, Kobayashi N, Okitsu T, Tanaka Y, Li SA, Chen Y, Miki A, Tanaka K, Nakaji S, Takei K., Soto-Gutierrez KA, Noguchi H, Lakey RT J., Leboulch P, Tanaka N, Yoon JW
    • Journal Title

      Nature Biotechnology 23(10)

      Pages: 1274-1282

    • NAID

      120002310224

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 糖尿病を標的とした細胞療法に向けたインスリン分泌ヒト細胞株の作成.2005

    • Author(s)
      小林直哉
    • Journal Title

      今日の移植 18(4)

      Pages: 429-434

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A human β-cell line for transplantation therapy to control type 1 diabetes.2005

    • Author(s)
      Michiki Narushima
    • Journal Title

      Nature Biotechnology 20(10)

      Pages: 1274-1282

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Maintenance of glucose-sensitive insulin secretion of cryopreserved human islets with University of Wisconsin solution and ascorbic acid-2 glucoside.2004

    • Author(s)
      Takashi Arata
    • Journal Title

      Artificial Organs 28(6)

      Pages: 529-536

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Development of a porcine model of type 1 diabetes by total pancreatectomy and establishment of a glucose tolerance evaluation method.2004

    • Author(s)
      Kazuya Kobayashi
    • Journal Title

      Artificial Organs 28(11)

      Pages: 1035-1042

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Transduction of human islets with the lentiviral vector.2004

    • Author(s)
      Naoya Kobayashi
    • Journal Title

      Transplantation Proceedings 36(7)

      Pages: 2203-2204

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Maintenance of glucose-sensitive insulin secretion of cryopreserved human islets with University of Wisconsin solution and ascorbic acid-2 glucoside.2004

    • Author(s)
      Arata T, Okitsu T, Fukazawa T, Ikeda H, Kobayashi K, Chen Y, Kosaka Y, Narushima M, Matsuoka J, Yamamoto I, Tanaka N, Lakey RT J, Kobayashi N
    • Journal Title

      Artificial Organs 28(6)

      Pages: 529-536

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Development of a porcine model of type 1 diabetes by total pancreatectomy and establishment of a glucose tolerance evaluation method.2004

    • Author(s)
      Kobayashi K, Kobayashi N, Okitsu T, Chen Y, Fukazawa T, Ikeda H, Kosaka Y, Narushima M, Arata T, Tanaka N
    • Journal Title

      Artificial Organs 28(11)

      Pages: 1035-1042

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Transduction of human islets with the lentiviral vector.2004

    • Author(s)
      Kobayashi N, Arata T, Okitsu T, Ikeda H, Kobayashi K, Kosaka Y, Narushima M, Tanaka N, Lakey RT J
    • Journal Title

      Transplantation Proceedings 36(7)

      Pages: 2203-2204

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Maintenance of glucose-sensitive insulin secretion of cryopreserved human islets with university of Wisconsin solution and ascorbic acid-2 glucoside.2004

    • Author(s)
      Takashi Arata
    • Journal Title

      Artificial Organs 28(6)

      Pages: 529-536

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Transduction of Human Islets With the Lentiviral Vector2004

    • Author(s)
      Naoya Kobayashi
    • Journal Title

      Transplantation Proceedings 36

      Pages: 2203-2204

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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