Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1
Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1
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DOI：
10.1002/hep.26254
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发表时间：
2013-06-01
期刊：
影响因子：
13.5
通讯作者：
Geisler, Fabian
中科院分区：
文献类型：
--
作者：
Jeliazkova, Petia;Joers, Simone;Geisler, Fabian
通过 Notch2 受体的 Notch 信号传导对于肝脏发育过程中正常的胆管生成至关重要。然而，对于该过程至关重要的 Notch2 下游信号事件的定义还不太明确。此外，Notch 信号传导是否也是成体肝细胞命运决定的基础尚不清楚。通过实施不同的遗传小鼠模型，我们提供了全面的分析，定义了Notch在发育中和成年肝脏中细胞命运控制中的作用。我们发现Notch2IC (N2IC)转基因对Notch2信号的细胞特异性激活导致胚胎成肝细胞快速胆管特异化，而且当在6个月大的成人肝脏中表达时，Notch2信号传导迅速将成人肝细胞重新编程为胆管细胞，形成管状囊性结构。当专门针对成人胆道和兼性肝脏祖细胞区室时，Notch2 能够诱导导管反应。此外，我们还描述了正常发育期间和 N2IC 表达模型中典型 Notch 信号传导的关键效应子的重要性。我们证明，胚胎发育过程中肝内胆管的小管形成以及 N2IC 诱导的胚胎成肝细胞的规范和形态发生以及成年肝细胞的胆汁转化都严重依赖于通过重组信号结合蛋白（RBP）-J 的经典 Notch 信号传导，但不需要 Hes1。结论：Notch2 似乎不仅是发育过程中胚胎成肝细胞胆汁定型的主要决定因素，也是成人肝细胞胆汁重编程的主要决定因素。胚胎成肝细胞和成体肝细胞中 Notch2 决定的细胞命运和形态发生依赖于经典的 Notch 信号传导，但不需要 Hes1。当胚胎信号通路活跃时，成体肝细胞具有显着的可塑性，可以承担新的细胞命运。 （肝病学 2013）
Notch signaling through the Notch2 receptor is essential for normal biliary tubulogenesis during liver development. However, the signaling events downstream of Notch2 critical for this process are less well defined. Furthermore, whether Notch signaling also underlies adult hepatic cell fate decisions is largely unknown. By implementing different genetic mouse models, we provide a comprehensive analysis that defines the role of Notch in cell fate control in the developing and adult liver. We show that cell-specific activation of Notch2 signaling by a Notch2IC (N2IC) transgene leads to rapid biliary specification of embryonic hepatoblasts, but alsowhen expressed in up to 6-month-old adult liversrapidly reprograms adult hepatocytes to biliary cells with formation of tubular-cystic structures. When directed specifically to the adult biliary and facultative liver progenitor cell compartment, Notch2 is capable of inducing a ductular reaction. Furthermore, we characterized the significance of key effectors of canonical Notch signaling during normal development and in N2IC-expressing models. We demonstrate that tubule formation of intrahepatic bile ducts during embryonic development as well as N2IC-induced specification and morphogenesis of embryonic hepatoblasts and biliary conversion of adult hepatocytes all critically rely on canonical Notch signaling via recombination signal binding protein (RBP)-J but do not require Hes1. Conclusion: Notch2 appears to be the main determinant not only of biliary commitment of embryonic hepatoblasts during development but also of biliary reprogramming of adult hepatocytes. Notch2-dictated cell fates and morphogenesis in both embryonic hepatoblasts and adult hepatocytes rely on canonical Notch signaling but do not require Hes1. Adult liver cells possess a remarkable plasticity to assume new cell fates when embryonic signaling pathways are active. (HEPATOLOGY 2013)