The basic helix-loop-helix transcription factor, Mist1, induces maturation of mouse fetal hepatoblasts.
The basic helix-loop-helix transcription factor, Mist1, induces maturation of mouse fetal hepatoblasts.
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DOI：
10.1038/srep14989
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发表时间：
2015-10-12
影响因子：
4.6
通讯作者：
Kamiya A
中科院分区：
文献类型：
--
作者：
Chikada H;Ito K;Yanagida A;Nakauchi H;Kamiya A
肝干/祖细胞，即肝母细胞，具有较高的增殖能力，可分化为成熟肝细胞和胆管细胞。因此，这些细胞被认为是有用的再生医学和肝脏疾病的药物筛选。然而，在目前的培养体系中，肝母细胞体外成熟不足是一个问题。本研究发现了一种新的诱导肝分化的调节因子，并在胚胎第13天的肝母细胞培养中，用成熟因子、抑癌素M和细胞外基质检测了该因子的分子功能。在这个培养体系中，基本螺旋-环-螺旋型转录因子Mist1的过表达诱导了成熟肝细胞标志物如氨甲酰磷酸合成酶1和几个细胞色素P450 （CYP）基因的表达。相反，Mist1抑制了胆管细胞标记物如Sox9、Sox17、Ck19和Grhl2的表达。Mist1显著诱导成肝细胞CYP3A代谢活性。此外，Mist1诱导富集肝脏的转录因子，CCAAT/增强子结合蛋白α和肝细胞核因子1α，这些已知参与肝功能。这些结果表明，Mist1部分诱导成熟肝细胞的表达和功能，同时伴有胆管细胞标志物的下调。
Hepatic stem/progenitor cells, hepatoblasts, have a high proliferative ability and can differentiate into mature hepatocytes and cholangiocytes. Therefore, these cells are considered to be useful for regenerative medicine and drug screening for liver diseases. However, it is problem that in vitro maturation of hepatoblasts is insufficient in the present culture system. In this study, a novel regulator to induce hepatic differentiation was identified and the molecular function of this factor was examined in embryonic day 13 hepatoblast culture with maturation factor, oncostatin M and extracellular matrices. Overexpression of the basic helix-loop-helix type transcription factor, Mist1, induced expression of mature hepatocytic markers such as carbamoyl-phosphate synthetase1 and several cytochrome P450 (CYP) genes in this culture system. In contrast, Mist1 suppressed expression of cholangiocytic markers such as Sox9, Sox17, Ck19, and Grhl2. CYP3A metabolic activity was significantly induced by Mist1 in this hepatoblast culture. In addition, Mist1 induced liver-enriched transcription factors, CCAAT/enhancer-binding protein α and Hepatocyte nuclear factor 1α, which are known to be involved in liver functions. These results suggest that Mist1 partially induces mature hepatocytic expression and function accompanied by the down-regulation of cholangiocytic markers.