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.

肝细胞（肝干细胞）被认为是肝细胞和胆道上皮细胞的常见前体。但是，它们的性质在很大程度上仍然未知。我们先前证明了小鼠肝类母细胞表达DLK/PERF1，具有EGF重复序列的细胞表面分子，并且使用抗DLK抗体分离出来，显示出与肝细胞和胆道上皮细胞在体外分离的。我们发现Notch2在肝母细胞中表达，其配体锯齿状1在形成胆管的门静脉周围的细胞中表达。此外，DLK+细胞中Notch活化形式的表达抑制了肝细胞对肝细胞的分化，并在体外增强了对胆道上皮细胞的分化。这些结果与锯齿状1负责阿拉吉综合征的发现相一致，该综合征表现出肝内胆管发育受损。总之，Notch信号对于从涂有层粘连蛋白和长期培养物的培养板中增殖的胎儿肝脏中分离出的肝脏+肝类细胞的分化很重要。这些细胞保留了区分肝细胞，胆汁上皮细胞以及具有胰腺基因表达的细胞的能力，这表明它们可能是多势内胚型祖细胞/干细胞。出现在严重受伤的肝脏区域的椭圆形细胞已被视为成年肝干细胞。因此，我们检查了DLK是否在椭圆形细胞中表达。通过使用大鼠模型，我们发现椭圆形细胞的子集表达了DLK，表明椭圆形细胞是异质的。

项目成果

Miyajima A.: "A possible role for CD4^+ thymic macrophages as professional scavengers of apoptotic thymocytes."thymocytes J.Immunol.Cutting Edge. 171. 2773-2777 (2003)

Miyajima A.：“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。”胸腺细胞 J.Immunol.Cutting Edge。

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.

Essential function of oncostatin M in nociceptive neurons of dorsal root ganglia

• DOI: 10.1523/jneurosci.4975-03.2004
• 发表时间: 2004-02-25
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Morikawa, Y;Tamura, S;Senba, E
• 通讯作者: Senba, E

Miyajima A.: "Cytokine regulation of liver development."Biochimica et Biophysica Acta. 1592. 303-312 (2003)

Miyajima A.：“肝脏发育的细胞因子调节”。生物化学和生物物理学学报。

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.