Sall4 Regulates Cell Fate Decision in Fetal Hepatic Stem/Progenitor Cells
Sall4 Regulates Cell Fate Decision in Fetal Hepatic Stem/Progenitor Cells
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DOI：
10.1053/j.gastro.2008.11.018
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发表时间：
2009-03-01
期刊：
影响因子：
29.4
通讯作者：
Nakauchi, Hiromitsu
中科院分区：
文献类型：
--
作者：
Oikawa, Tsunekazu;Kamiya, Akihide;Nakauchi, Hiromitsu
背景与目的：胎儿肝干/祖细胞，称为肝母细胞，可分化为肝细胞和胆管细胞。调控这一谱系分割过程的分子机制尚不清楚。Sall4已被证明是胚胎干细胞中器官发生、胚胎发生、多能性维持和早期胚胎细胞命运决定的调节因子之一。Sall4在肝脏发育过程中的表达和功能作用尚未阐明。我们在此提供它们在肝母细胞中的首次描述。方法：为了研究Sall4在胎儿肝脏发育中的功能，纯化胚胎第14天小鼠肝脏的Dlk(+)CD45(-)Ter119（-）肝母细胞，并采用逆转录病毒或慢病毒介导的基因转移进行体外功能的获得和丧失分析和体内移植分析。结果：我们发现Sall4在胎儿肝母细胞中表达，而在成人肝细胞中不表达。Sall4的表达水平在肝脏发育过程中逐渐下降。肝母细胞中过表达Sall4可显著抑制抑癌素M和细胞外基质诱导的体外成熟，这可以通过形态学改变和肝成熟标志基因表达的抑制来证明。当胶原凝胶包埋培养诱导胆管样结构时，Sall4的过表达显著增加了细胞角化蛋白19（+）分支结构的大小和数量。敲低Sall4抑制了这些分支结构的形成。在体内移植中，Sall4增强了移植肝母细胞衍生的细胞角化蛋白19(+)-胆管的分化。结论：这些结果表明，Sal14在控制肝母细胞谱系承诺中起着至关重要的作用，不仅抑制其向肝细胞分化，而且推动其向胆管细胞分化。
Background & Aims: Fetal hepatic stem/progenitor cells, called hepatoblasts, differentiate into both hepatocytes and cholangiocytes. The molecular mechanisms regulating this lineage segmentation process remain unknown. Sall4 has been shown to be among the regulators of organogenesis, embryogenesis, maintenance of pluripotency, and early embryonic cell fate decisions in embryonic stem cells. The expression and functional roles of Sall4 during liver development have not been elucidated. We here provide their first description in hepatoblasts. Methods: To investigate functions of Sall4 in fetal liver development, Dlk(+)CD45(-)Ter119(-) hepatoblasts derived from embryonic day 14 mouse livers were purified, and in vitro gain and loss of function analyses and in vivo transplantation analyses were performed using retrovirus- or lentivirus-mediated gene transfer. Results: We demonstrated that Sall4 was expressed in fetal hepatoblasts but not adult hepatocytes. The expression level of Sall4 gradually fell during liver development. Overexpression of Sall4 in hepatoblasts significantly inhibited maturation induced by oncostatin M and extracellular matrix in vitro, as evidenced by morphologic changes and suppression of hepatic maturation marker gene expression. When bile duct-like structures were induced by collagen gel-embedded culture, overexpression of Sall4 markedly augmented size and number of cytokeratin19(+)-branching structures. Knockdown of Sall4 inhibited formation of these branching structures. With in vivo transplantation, Sall4 enhanced differentiation of cytokeratin19(+)-bile ducts derived from transplanted hepatoblasts. Conclusions: These results suggest that Sal14 plays a crucial role in controlling the lineage commitment of hepatoblasts not only inhibiting their differentiation into hepatocytes but also driving their differentiation toward cholangiocytes.