Hirose Yoshikazu, Itoh Tohru, Miyajima Atsushi
Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan.
Exp Cell Res. 2009 Sep 10;315(15):2648-57. doi: 10.1016/j.yexcr.2009.06.018. Epub 2009 Jun 24.
Hedgehog (Hh) signaling plays crucial roles in development and homeostasis of various organs. In the adult liver, it regulates proliferation and/or viability of several types of cells, particularly under injured conditions, and is also implicated in stem/progenitor cell maintenance. However, the role of this signaling pathway during the normal developmental process of the liver remains elusive. Although Sonic hedgehog (Shh) is expressed in the ventral foregut endoderm from which the liver derives, the expression disappears at the onset of the liver bud formation, and its possible recurrence at the later stages has not been investigated. Here we analyzed the activation and functional relevance of Hh signaling during the mouse fetal liver development. At E11.5, Shh and an activation marker gene for Hh signaling, Gli1, were expressed in Dlk(+) hepatoblasts, the fetal liver progenitor cells, and the expression was rapidly decreased thereafter as the development proceeded. In the culture of Dlk(+) hepatoblasts isolated from the E11.5 liver, activation of Hh signaling stimulated their proliferation and this effect was cancelled by a chemical Hh signaling inhibitor, cyclopamine. In contrast, hepatocyte differentiation of Dlk(+) hepatoblasts in vitro as manifested by the marker gene expression and acquisition of ammonia clearance activity was significantly inhibited by forced activation of Hh signaling. Taken together, these results demonstrate the temporally restricted manner of Hh signal activation and its role in promoting the hepatoblast proliferation, and further suggest that the pathway needs to be shut off for the subsequent hepatic differentiation of hepatoblasts to proceed normally.
刺猬信号通路（Hh）在多种器官的发育和内环境稳定中发挥着关键作用。在成年肝脏中，它调节多种细胞类型的增殖和/或活力，尤其是在损伤条件下，并且还与肝干细胞/祖细胞的维持有关。然而，该信号通路在肝脏正常发育过程中的作用仍不清楚。尽管音猬因子（Shh）在肝脏起源的腹侧前肠内胚层中表达，但在肝芽形成开始时其表达消失，且尚未研究其在后期阶段是否可能再次出现。在此，我们分析了小鼠胚胎肝脏发育过程中Hh信号通路的激活及其功能相关性。在胚胎第11.5天（E11.5），Shh和Hh信号通路的激活标记基因Gli1在Dlk（+）成肝细胞（胎儿肝脏祖细胞）中表达，随着发育进程，此后该表达迅速下降。在从E11.5肝脏分离的Dlk（+）成肝细胞培养物中，Hh信号通路的激活刺激了它们的增殖，而这种作用被化学Hh信号通路抑制剂环杷明所消除。相反，Hh信号通路的强制激活显著抑制了Dlk（+）成肝细胞在体外以标记基因表达和氨清除活性获得为表现的肝细胞分化。综上所述，这些结果证明了Hh信号激活的时间限制方式及其在促进成肝细胞增殖中的作用，并进一步表明该信号通路需要关闭，以使成肝细胞随后的肝脏分化正常进行。
