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The analysis for proliferation and differentiation of hepatic stem cells

Research Project

Project/Area Number 13470121
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionYamaguchi University

Principal Investigator

OKITA Kiwamu  Yamaguchi University, School of Medicine Department of Gastroenterlogy & Hepatlogy, Professor, 医学部, 教授 (70107738)

Co-Investigator(Kenkyū-buntansha) TERAI Shuji  Yamaguchi University, School of Medicine, Research Associate, 医学部, 助手 (00332809)
SAKAIDA Isao  Yamaguchi University, School of Medicine, Associate Professor, 医学部, 講師 (80263763)
萱野 幸三  山口大学, 医学部, 助手 (90314799)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥16,300,000 (Direct Cost: ¥16,300,000)
Fiscal Year 2003: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2002: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 2001: ¥5,900,000 (Direct Cost: ¥5,900,000)
KeywordsHepatic stem cell / Differentiation / Cancer stem cell / Extra cellular matrix / Hepatocarcinogeneisis / Bone marrow cell / Niche / Cell therapy / 幹発癌 / 増殖 / 可塑性
Research Abstract

Here we found that persistent injury induced efficient trans-differentiation of BMCs into functional hepatocytes. Liver cirrhosis mice induced by carbon tetrachloride were injected with 1x10^5 non-treated green fluorescent protein (GFP)-positive BMCs via tall vein. In these mice, transplanted GFP-positive BMCS efficiently migrated into the peri-portal area of liver lobules after one day and repopulated one-fourth of the recipient liver by 4 weeks. In contrast, no GFP-positive BMCs were detected following transplantation into control mice. with undamaged livers. BMCs trans-differentiated into functional mature hepatocytes via immature hepatoblasts. Serum albumin was significantly elevated to compensate for chronic liver failure by BMC transplantation. These results showed that the recipient condition and microenvironments are key factors for successful cell therapy using BMC. We named this model as a GFP/CC14 model. As the next step, we developed a new monoclonal antibody, anti-Liv8 usi … More ng mouse fetal liver antigen. On embryonic day 11.5, Liv8-positive cells were seen in the liver of wild-tape, but not AML1 knockout mice, which lack the hematopoietic system. Liv8-positive cells accounted for 32% of the BMC in adult mice and included CD45-positive cells. We separated Liv8-positive or Liv8-negative cells using Auto Magnetic Cell Sorting system, and then transplanted these cells to a continuous liver damaged model. After one week, there was no marked difference in the initial colonization of BMC in the liver between recipients of Liv8-positive and Liv8-negative cells, but at 4 weeks more efficient BMC trans-differentiation into hepatocytes was seen with Liv8-negative cells. Now we are trying to identify the antigen of anti-Liv8. These analysis will be useful to develop all efficient cell therapy to repair damaged liver. On the other hands, we identified that new protein. Human homologue of maid (HHM) is a helix-loop-helix (HLH) transcriptional regulatory protein that is involved in the hepatic stem cell development and differentlation. We analyzed the potential involvement of HHM in hepatocarcinogenesis. We assessed HHM expression in the chorine deficient L-amino acid defined (CDAA) diet model of rat hepatocarcinogenesis by in situ hybridization DISH), and human HCC samples by immunohistochemical analysis. High HHM expression was seen in foci and HCC. These results suggested that HHM may be a useful marker protein to detect initiation of hepatocarcinogenesis Less

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Yamamoto N: "A subpopulation of bone marrow cells depleted by a novel antibody, anti-Liv8,is useful for cell therapy to repair damaged liver."Biochem Biophys Res Commun.. 23;313(4). 1110-1118 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Terai S: "An in vivo model for monitoring trans-differentiation of bone marrow cells into functional hepatocytes."J Biochem. 134(4). 551-558 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Horie T: "L-cysteine administration prevents liver fibrosis by suppressing hepatic stellate cell proliferation and activation."Biochem Biophys Res Commun.. 305(1). 94-100 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Terai S: "New cell therapy using bone marrow cell to repair damaged liver."J Gastroenterology. 37(Suppl XIV). 162-163 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sakaida I: "Transplantation of bone marrow cells reverse CCl4-induced liver fibrosis."Hepatology. 36-4. 295-295 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Terai S: "Strategy for the development of cell therapy using bone marrow cells to repair damaged liver. Growth/Differentiation and hepatocyte/HCC"Frontier in Hepatology (Stem cell and liver regeneration). 6 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yamamoto N: "A subpopulation of bode marrow cells depleted by a novel antibody, anti-Liv8, is useful for cell therapy to repair damaged liver"Biochem Biophys Res Commun. 23 : 313(4). 1110-1118 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Terai S: "An in vivo model for monitoring trans-differentiation of bone marrow cells into functional hepatocytes"J Biochem. 134(4). 551-558 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Horie T: "L-cysteine administration prevents liver fibrosis by suppressing hepatic stellate cell proliferation and activation"Biochem Biophys Res Commun. 305(1). 94-100 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Terai S: "New cell therapy using bone marrow cell to repair damaged liver"J Gastroenterology. p37(SupplXIV). 162-163 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sakaida I: "Transplantation of bone marrow cells reverse CCl4-induced liver fibrosis"Hepatology. 36-4. 295-295 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Terai S: "Strategy for die development of cell therapy using bone marrow cells to repair damaged liver. Growth/Differentiation and hepatocyte/HCC"Frontier in Hepatology (Stem cell and liver regeneration). 6. (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sakaida I: "Herbal medicine Sho-saiko-to (TJ-9) increases expression matrix metalloproteinases (MMPs) with reduced expression of tissue inhibitor of metalloproteinases (TIMPs) in rat stellate cell"Life Science. 19;74(18). 2251-2263 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamamoto N: "A subpopulation of bone marrow cells depleted by a novel antibody, anti-Liv8, is useful for cell therapy to repair damaged liver"Biochem Biophys Res Commun.. 23;313(4). 1110-1118 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Terai S: "An in vivo model for monitoring trans-differentiation of bone marrow cells into functional hepatocytes"J Biochem. 134(4). 551-558 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takashima M: "Proteomic profiling of heat shock protein 70 family members as biomarkers for hepatitis C virus-related hepatocellular carcinoma"Proteomics. 3(12). 2487-2493 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sakaida I: "Leptin receptor-deficient Zucker (fa/fa) rat retards the development of pig serum-induced liver fibrosis with Kupffer cell dysfunction"Life Sci.. 73(19). 2491-2501 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Horie T: "L-cysteine administration prevents liver fibrosis by suppressing hepatic stellate cell proliferation and activation"Biochem Biophys Res Commun.. 305(1). 94-100 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Terai S: "Frontier in Hepatology (Stem cell and liver regeneration)"Strategy for the development of cell therapy using bone marrow cells to repair damaged liver. Growth/Differentiation and hepatocyte/HCC. 51-56 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shuji Terai: "New cell therapy using bone marrow cell to repair damaged liver"J Gastroenterology. 37(SupplXIV). 162-163 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Isao Sakaida: "Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrix metalloproteinases (MMPs) of Kupffer cells"Life Sci. 72-8. 943-959 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hitoshi Shirahashi: "Ubiquitin is a possible new predictive marker for the recurrence of human hepatocellular carcinoma"Liver. 22-5. 413-418 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shuji Terai: "The strategy for development of cell therapy using bone marrow cell to repair damaged liver"Hepatology. 36-4. 200-200 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kaoru Omori: "Gene expression profile which regulates the differentiation of bone marrow cell into hepatocyte in GFP/CCl4 model"Hepatology. 36-4. 199-199 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Isao sakaida: "Transplantation of bone marrow cells reverse CCl4-induced liver fibrosis"Hepatology. 36-4. 295-295 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shuji Terai: "Growth, Proliferation and Apoptosis in Hepatocyte"Springer Verlag. 9 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Terai S: "New cell therapy using bone marrow cell to repair damaged liver."J of Gastroenterology. (印刷中). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Terai S: "Development of new regenerative model : transplanted GFP positive bone marrow cell migrated into damaged area and differentiated into hepatocyte."Hepatology. 235. 34 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 寺井崇二: "肝幹細胞の発生・分化・増殖に関与する転写制御分子HHMの同定と機能解析"肝胆膵. (印刷中). (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shuji Terai: "Growth, Proliferation and Apoptosis in Hepatocyte"Springer Verlag. 9 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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