Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors
Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors
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DOI：
10.1242/jcs.01169
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发表时间：
2004-07-01
影响因子：
4
通讯作者：
Miyajima, A
中科院分区：
文献类型：
--
作者：
Tanimizu, N;Miyajima, A
成肝细胞既能产生成熟的肝细胞，又能产生胆管细胞。虽然Notch信号与由胆管细胞组成的胆管的形成有关，但对肝母细胞的谱系承诺机制知之甚少。在这里，我们描述了Notch通路在肝母细胞分化中的作用。免疫组织化学分析显示，Jagged1在门静脉周围的细胞中表达，Notch2在妊娠中期门静脉周围形成导管板的大部分肝细胞中表达。有趣的是，Jagged1(+)细胞与胆管板相邻，这表明Notch信号在分化为胆管细胞的肝母细胞中被激活。事实上，在DLK(+)肝母细胞中表达Notch胞内域抑制了肝分化，并显著降低了白蛋白的表达，白蛋白是肝母细胞和肝细胞的标志物。此外，在肝母细胞培养中加入Matrigel可上调已知在胆管细胞中表达的细胞角蛋白7和19、整合素β4和HNF1β的表达。相反，针对Notch2mRNA的siRNA和伽马分泌酶抑制剂L-685,458下调了Notch信号转导，促进了肝脏分化。与先前发现的成熟胆管细胞强烈表达HNF1β，但几乎不表达HNF1α、HNF4和C/EBPalpha的结果一致，激活Notch信号上调了HNF1β的表达，而下调了HNF1α、HNF4和C/EBPalpha的表达。这些结果表明，Notch信号有助于形成一个适合胆管细胞分化的转录因子网络。
Hepatoblasts give rise to both mature hepatocytes and cholangiocytes. While Notch signaling has been implicated in the formation of bile ducts composed of cholangiocytes, little is known about the mechanism of lineage commitment of hepatoblasts. Here we describe the role of the Notch pathway in hepatoblast differentiation. Immunohistochemical analysis showed that Jagged1 was expressed in the cells surrounding the portal veins and Notch2 was expressed in most hepatic cells at mid gestation when ductal plates are formed surrounding the portal veins. Interestingly, the Jagged1(+) cells were adjacent to ductal plates, suggesting that the Notch signaling is activated in hepatoblasts that undergo differentiation into cholangiocytes. In fact, expression of the Notch intracellular domain in Dlk(+) hepatoblasts inhibited hepatic differentiation and significantly reduced the expression of albumin, a marker of both hepatoblasts and hepatocytes. Furthermore, the addition of Matrigel to the hepatoblast culture upregulated the expression of cytokeratin 7 and 19, integrin beta4, and HNF1beta, which are known to be expressed in cholangiocytes. By contrast, downregulation of the Notch signaling by siRNA specific for Notch2 mRNA as well as by the gamma-secretase inhibitor L-685,458 promoted the hepatic differentiation. Consistent with the previous finding that mature cholangiocytes strongly express HNF1beta, but barely express HNF1alpha, HNF4, and C/EBPalpha., activation of the Notch signaling upregulated HNF1beta expression, whereas it downregulated the expression of HNF1alpha., HNF4, and C/EBPalpha. These results suggest that the Notch signaling contributes to form a network of these transcription factors suitable for cholangiocyte differentiation.