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Studies of regenerative medicine on differentiation into hepatic and bile duct cells for preclinical trial to surgery

Research Project

Project/Area Number 18390343
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionTokyo Medical and Dental University

Principal Investigator

TERAOKA Hirobumi (2007)  Tokyo Medical and Dental University, Medical Research Institute, Professor (30019137)

寺本 研一 (2006)  東京医科歯科大学, 大学院医歯学総合研究科, 助教授 (80197813)

Co-Investigator(Kenkyū-buntansha) ARII Shigeki  Tokyo Medical and Dental University, Graduate School of Medicine, Professor (50151171)
TANAKA Yujiro  Tokyo Medical and Dental University, Graduate School of Medicine, Professor (70236644)
ISEKI Sachiko  Tokyo Medical and Dental University, Graduate School of dentistry, Assistant Professor (80251544)
YOSHIOKA Kenichi  Tokyo Medical and Dental University, Medical Research Institute, Assistant Professor (70321916)
TAKASE Kozo  Tokyo Medical and Dental University, Graduate School of Medicine, Professor (90211333)
斉藤 佳子  東京医科歯科大学, 難治疾患研究所, 教務職員 (50178969)
朝比奈 欣治  東京医科歯科大学, 難治疾患研究所, 助手 (40345294)
寺岡 弘文  東京医科歯科大学, 難治疾患研究所, 教授 (30019137)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥17,390,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥2,190,000)
Fiscal Year 2007: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
Fiscal Year 2006: ¥7,900,000 (Direct Cost: ¥7,900,000)
KeywordsES cell / Hepatocyte / Regenerative medicine / Cell transplantation / Bile duct / Hepatoblast / ex utero surgery / iPS cell / 肝機能障害治療 / 肝外胆管
Research Abstract

Although the intrahepatic bile duct has been suggested to be a source of hepatic progenitor cells in the severely damaged liver, little attention has been paid to the question of whether hepatic progenitor cells exist in the extrahepatic bile duct (EHBD). We examined the phenotypic changes of the mouse EHBD following the bile duct ligation. After bile duct ligation, the number of c-kit-positive epithelilal cells increased in the EHBD. The ligated EHBD expressed mRNA for hepatic progenitor cell markers. Hepatocyte markers were also transiently detected in the EHBD and gall bladder after a bile duct ligation. Hepatic progenitor cells positive for both c-kit and albumin were found in the cultured EHBD population. These results suggest a potential of the EHBD and gall bladder as useful transplantable sources for liver injury.
Avoiding the limitations of the adult liver niche, transplantation of hepatic stem/progenitor cells into fetal liver is desirable to analyze immature cells in a hepati … More c developmental environment. Here, we established a new monitor tool for cell fate of hepatic progenitor cells transplanted into the mouse fetal liver by using ex utero surgery. When embryonic day (ED) 14.5 hepatoblasts were injected into the ED14.5 fetal liver, the transplanted cells expressed albumin abundantly or α-fetoprotein weakly, and contained glycogen in the neonatal liver, indicating that transplanted hepatoblasts can proliferate and differentiate in concord with surrounding recipient parenchymal cells. The transplanted cells became mature in the liver of 6-week-old mice. Furthermore, this method was applicable to transplantation of hepatoblast-like cells derived from mouse ES cells. These data indicate that this unique technique will provide a new in vivo experimental system for studying cell fate of hepatic stem/progenitor cells and liver organogenesis.
We revealed involvement of VEGF in efficient differentiation into hepatocyte-like cells, biological function of the undifferentiated cell marker gene DPPA4, and epigenetic regulation of the mature hepatocyte marker gene MAT1A. Less

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report

Research Products

(24 results)

All 2009 2008 2007 2006 Other

All Journal Article (17 results) (of which Peer Reviewed: 6 results) Presentation (2 results) Book (3 results) Remarks (2 results)

  • [Journal Article] A novel method of mouse ex utero transplantation of hepatic progenitor cells into the fetal liver2009

    • Author(s)
      Shikanai M, et al.
    • Journal Title

      Biochem. Biophys. Res. Commun. 381

      Pages: 276-282

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] A novel method of mouse ex utero transplantation of hepatic progenitor cells into the fetal liver2009

    • Author(s)
      Shikanai M, Asahina K, Iseki S, Teramoto K, Nishida T, Saito T, Shimizu-Saito K, Ota M, Eto K, Teraoka H
    • Journal Title

      Biochemical and Biophysical Research Communications 381

      Pages: 276-282

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] VEGF promotes proliferation and function of hepatocyte-like cells in embryoid bodies formed from mouse embryonic stem cells2008

    • Author(s)
      Fujimori H, et al.
    • Journal Title

      J. Hepatol. 48

      Pages: 962-973

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Involvement of CCAAT/enhancer binding protein-β in epigenetic regulation of mouse methionine adenosyltransferase 1A gene expression2008

    • Author(s)
      Ikeda R, et al.
    • Journal Title

      Intern. J. Biochem. Cell Biol. 40

      Pages: 1956-1969

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] VEGF promotes proliferation and function of hepatocyte-like cells in embryoid bodies formed from mouse embryonic stem cell2008

    • Author(s)
      Fujimori H, Asahina K, ShimizirSaito K, Ikeda R, Tanaka Y, Teramoto K, Morita I, Teraoka H
    • Journal Title

      Journal of Hepatology 48

      Pages: 962-973

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Involvement of CCAAT/enhancer binding protein-p in epigenetic regulation of mouse methionine adenosyltransferase 1A gene expression2008

    • Author(s)
      Ikeda R, Nishida T, Watanabe F, Shimizu-Saito K, Asahina K, Horikawa S, Teraoka H
    • Journal Title

      International Journal of Biochemistry and Cell Biology 40

      Pages: 1956-1969

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Human cord blood cells transplanted into chronic-damaged liver exhibit similar characteristics to functional hepatocytes2007

    • Author(s)
      Kakinuma S, et al.
    • Journal Title

      Transplant. Proc. 39

      Pages: 240-243

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary 2006 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hepatic progenitor cells in the mouse extrahepatic bile duct after a bile duct ligation2007

    • Author(s)
      Irie T, et al.
    • Journal Title

      Stem Cells Develop. 16

      Pages: 979-987

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Developmental pluripotency-associated 4 localized in active chromatin inhibits mouse embryonic stem cell differentiation into a primitive ectoderm lineage2007

    • Author(s)
      Masaki H, et al.
    • Journal Title

      J. Biol. Chem. 282

      Pages: 33034-33042

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Human cord blood cells transplanted into chronic-damaged liver exhibit similar characteristics to functional hepatocytes.2007

    • Author(s)
      Kakinuma S, Asahina K, Okamura K, Teramoto K, Tateno C, Yoshizato K, Tanaka Y, Yasumizu T, Sakamoto N, Watanabe M, Teraoka H
    • Journal Title

      Transplantation Proceedings 39

      Pages: 240-243

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Hepatic progenitor cells in the mouse extrahepatic bile duct after a bile ductligation2007

    • Author(s)
      Irie T, Asahina K, Shimizu-Saito K, Teramoto K, Arii S, Teraoka H
    • Journal Title

      Stem Cells and Development 16

      Pages: 979-987

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Developmental pluripotency associated 4 (Dppa4) localized in active chromatin inhibits mouse embryonic stem cell differentiation into a primitive ectoderm lineage2007

    • Author(s)
      Masaki H, Nishida T, Kitajima S, Asahina K, Teraoka H
    • Journal Title

      Journal of Biological Chemistry 282

      Pages: 33034-33042

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Transplantation of embryonic stem cell-derived hepatocytes and risk of teratoma formation.2007

    • Author(s)
      Asahina K, Teramoto K, Arii S, Teraoka H
    • Journal Title

      in STEM CELLS AND CANCER (ed. by Parsons DW), Nova Publishers

      Pages: 1-22

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Transplantation of embryonic stem cell-derived heoatocytes and risk of teratoma formation2007

    • Author(s)
      Asahina K., et al.
    • Journal Title

      Stem Cells and Cancer (ed. by Parsons DW), Nova Publishers In press

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Generation of hybrid hepatocytes by cell fusion from monkey embryoid body cells in the injured mouse liver2006

    • Author(s)
      Okamura K, et al.
    • Journal Title

      Histochem. Cell Biol. 125

      Pages: 247-257

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Embryonic stem cells : Hepatic differentiation and regenerative medicine fro the treatment of liver disease.2006

    • Author(s)
      Asahina K., et al.
    • Journal Title

      Curr. Stem Cell Res. Ther. 1

      Pages: 139-156

    • Related Report
      2006 Annual Research Report
  • [Journal Article] カニクイザルES細胞からの肝細胞分化誘導 I. ヒトおよびサルのES細胞2006

    • Author(s)
      岡村健太郎, ら
    • Journal Title

      再生医療 5

      Pages: 52-58

    • Related Report
      2006 Annual Research Report
  • [Presentation] VEGF promotes hepatocyte differentiation in embryoid bodies formed from mouse embryonic stem cells2006

    • Author(s)
      Asahina K, Fujimori H, Shimizu-Saito K, Teraoka H
    • Organizer
      2006 FASEB Summer Research Conferences Liver Growth, Development & Disease
    • Place of Presentation
      Snowmass Village, CO, USA
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Hepatocyte differentiation and eratoma formation after transplantation of embryoid body cells derived from murine and primate embryonic stem cells into injured mouse liver2006

    • Author(s)
      Teramoto K, Asahina K, Okamura K, Kumashiro Y, Me T, Shimizu-Saito K, Teraoka H, Arii S
    • Organizer
      World Transplant Congress, Hynes Convention Center
    • Place of Presentation
      Boston, MA, USA
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] Stem Cells and Cancer, Chapter 1 : Transplantation of embryonic stem cell derived heoatocytes and risk of teratoma formation2007

    • Author(s)
      Asahina K, et al.
    • Total Pages
      22
    • Publisher
      Nova Publishers, Inc.
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] Stem Cells and Cancer, Chapter 1 : Transplantation of embryonic stem cell-derived heoatocytes and risk of teratoma formation2007

    • Author(s)
      Asahina K, et al.
    • Total Pages
      22
    • Publisher
      Nova Publishers, Inc.
    • Related Report
      2007 Annual Research Report
  • [Book] サイトプロテクション-ES細胞からの肝細胞分化誘導2006

    • Author(s)
      寺本研一, ら
    • Total Pages
      5
    • Publisher
      癌と化学療法社
    • Related Report
      2006 Annual Research Report
  • [Remarks] 「研究成果報告書概要(和文)」より

    • URL

      http://www.tmd.ac.jp/mri/pbc/hyoushi.html

    • Related Report
      2007 Final Research Report Summary
  • [Remarks]

    • URL

      http://www.tmd.ac.jp/mri/pbc/hyoushi.html

    • Related Report
      2007 Annual Research Report

URL: 

Published: 2006-03-31   Modified: 2016-04-21  

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