| Project/Area Number |
15027202
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | The University of Tokyo |
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Principal Investigator |
MIYAJIMA Atsushi The University of Tokyo, Institute of Molecular and Cellular Biosciences, Professor, 分子細胞生物学研究所, 教授 (50135232)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Minoru The University of Tokyo, Institute of Molecular and Cellular Biosciences, Research Assosiate, 分子細胞生物学研究所, 助手 (80321909)
SEKINE Keisuke The University of Tokyo, Institute of Molecular and Cellular Biosciences, Research Assosiate, 分子細胞生物学研究所, 助手 (00323569)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥59,000,000 (Direct Cost: ¥59,000,000)
Fiscal Year 2004: ¥29,500,000 (Direct Cost: ¥29,500,000)
Fiscal Year 2003: ¥29,500,000 (Direct Cost: ¥29,500,000)
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| Keywords | Development / Liver / Differentiation / Stem cell / Liver injury / Cell surface antigen / Regeneration / Signal / 文化 / Notch / サイトカイン / シグナル伝達 / 上皮細胞 |
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| Research Abstract |
Hepatoblasts (hepatic stem cells) are considered to be the common precursor for hepatocytes and biliary epithelial cells. However, their nature remains largely unknown. We previously demonstrated that mouse hepatoblasts express Dlk/Pref1, a cell surface molecule with EGF repeats, and hepatoblasts isolated by using anti-Dlk antibody were shown to differentiate to hepatocytes and biliary epithelial cells in vitro. We found that Notch2 was expressed in hepatoblasts and its ligand Jagged-1 was expressed in the cells surrounding the portal vein where bile ducts are formed. Moreover, expression of an activated form of Notch in Dlk+ cells suppressed the differentiation of hepatoblasts to hepatocytes and enhanced the differentiation to biliary epithelial cells in vitro. These results are consistent with the finding that Jagged-1 is responsible for the Alagille syndrome that exhibits impaired development of intrahepatic bile ducts. In conclusion, Notch signaling is important for the differentiation of hepatoblasts.
Dlk+ hepatoblasts isolated from fetal liver proliferated in a culture plate coated with laminin and long-term culture was reproducibly established. These cells retained the ability to differentiate to hepatocytes, biliary epithelial cells and also cells with pancreatic gene expression, suggesting that they may be multipotential endodermal progenitors/stem cells.
Dlk expression declines along with hepatic development and is completely absent in adult liver. Oval cells that appear in portal area of severely injured liver have been considered as adult liver stem cells. We therefore examined if Dlk is expressed in oval cells. By using a rat model we found that a subset of oval cells expressed Dlk, indicating that oval cells are heterogeneous.
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