Molecular mechanism of proliferation and differentiation of hepatocyte.

肝细胞增殖分化的分子机制。

• 批准号: 15027202
• 负责人: MIYAJIMA Atsushi
• 金额: $ 37.76万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15027202/
• 关键词: 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

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.

肝母细胞(肝干细胞)被认为是肝细胞和胆管上皮细胞的共同前体。然而，它们的性质在很大程度上仍不清楚。我们已经证实，小鼠肝母细胞表达具有EGF重复序列的细胞表面分子DLK/Pref1，用抗DLK抗体分离的肝母细胞在体外可以分化为肝细胞和胆管上皮细胞。我们发现Notch2在肝母细胞中表达，其配体Jagge-1在门静脉周围形成胆管的细胞中表达。此外，在DLK+细胞中表达活化形式的Notch抑制了肝母细胞向肝细胞的分化，促进了向胆管上皮细胞的分化。这些结果与Jagge-1导致Alagille综合征的发现是一致的，Alagille综合征表现为肝内胆管发育受损。结论：Notch信号转导通路在肝母细胞分化过程中起重要作用。从胎肝分离的DLK+肝母细胞在包被层粘连蛋白的培养板中增殖，并可进行长期培养。这些细胞保留了分化为肝细胞、胆管上皮细胞以及表达胰腺基因的细胞的能力，提示它们可能是多潜能内皮祖细胞/干细胞。随着肝脏的发育，DLK的表达逐渐下降，在成年肝脏中完全缺失。出现在严重损伤肝脏汇管区的卵圆细胞被认为是成人肝干细胞。因此，我们检查了DLK是否在卵圆细胞中表达。通过使用大鼠模型，我们发现部分卵圆细胞表达DLK，表明卵圆细胞是异质性的。

项目成果

A possible role for CD4^+ thymic macrophages as professional scavengers of apoptotic thymocytes

CD4^胸腺巨噬细胞作为凋亡胸腺细胞专业清道夫的可能作用

• 发表时间: 2003
• 期刊: J. Immunol. Cutting Edge 171
• 作者: Esashi E. et al.

Development of CD4+ macrophages from intrathymic T cell progenitors is induced by thymic epithelial cells

• DOI: 10.4049/jimmunol.173.7.4360
• 发表时间: 2004-10-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Esashi, E;Ito, H;Miyajima, A
• 通讯作者: Miyajima, A

Miyajima A.: "Oncostatin M promotes differentiation of fetal hepatocytes in vitro and regulates liver regeneration in vivo."Frontier in hepatology: growth/differentiation and hepatocyte/HCC. in press.

Miyajima A.：“制瘤素 M 在体外促进胎儿肝细胞分化，并在体内调节肝脏再生。”肝病学前沿：生长/分化和肝细胞/HCC。

Miyajima A.: "Isolation of hepatoblasts based on the expression of Dlk/Pref-1."J.Cell Sci.. 116. 1775-1786 (2003)

Miyajima A.：“基于 Dlk/Pref-1 表达的成肝细胞的分离。”J.Cell Sci.. 116. 1775-1786 (2003)

Neuronal leucine-rich repeat protein 4 is required for hippocampus-dependent long-lasting memory.

神经元富含亮氨酸的重复蛋白 4 是海马依赖性持久记忆所必需的。

• 发表时间: 2005
• 期刊: Mol. Cell Biol. 25
• 作者: Bando T.;Sekine K.;Kobayashi S.;Watanabe A.;Rump A.;Tanaka M.;Suda Y.;Kato S.;Manabe T.;Miyajima A.
• 通讯作者: Miyajima A.