Department of Cell and Developmental Biology and Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
Hepatology. 2010 Apr;51(4):1391-400. doi: 10.1002/hep.23431.
Alagille syndrome, a chronic hepatobiliary disease, is characterized by paucity of intrahepatic bile ducts (IHBDs). To determine the impact of Notch signaling specifically on IHBD arborization, we studied the influence of both chronic gain and loss of Notch function on the intact three-dimensional IHBD structure using a series of mutant mouse models and a resin casting method. Impaired Notch signaling in bipotential hepatoblast progenitor cells (BHPCs) dose-dependently decreased the density of peripheral IHBDs, whereas activation of Notch1 results in an increased density of peripheral IHBDs. Although Notch2 has a dominant role in IHBD formation, there is also a redundant role for other Notch receptors in determining the density of peripheral IHBDs. Because changes in IHBD density do not appear to be due to changes in cellular proliferation of bile duct progenitors, we suggest that Notch plays a permissive role in cooperation with other factors to influence lineage decisions of BHPCs and sustain peripheral IHBDs.
There is a threshold requirement for Notch signaling at multiple steps, including IHBD tubulogenesis and maintenance, during hepatic development that determines the density of three-dimensional peripheral IHBD architecture.
Alagille 综合征是一种慢性肝胆疾病，其特征是肝内胆管（IHBDs）稀少。为了确定 Notch 信号通路对 IHBD 分支的具体影响，我们使用一系列突变体小鼠模型和树脂铸造方法，研究了 Notch 功能的慢性获得和丧失对完整的三维 IHBD 结构的影响。双潜能肝祖细胞（BHPCs）中 Notch 信号的受损会使周围 IHBD 的密度呈剂量依赖性降低，而 Notch1 的激活则会导致周围 IHBD 的密度增加。尽管 Notch2 在 IHBD 形成中起主导作用，但其他 Notch 受体在决定周围 IHBD 的密度方面也具有冗余作用。由于 IHBD 密度的变化似乎不是由于胆管祖细胞的细胞增殖变化引起的，我们认为 Notch 与其他因素一起发挥许可作用，影响 BHPC 的谱系决定，并维持周围 IHBD。
在肝发育过程中，Notch 信号在包括 IHBD 小管形成和维持在内的多个步骤中存在一个阈值要求，这决定了三维周围 IHBD 结构的密度。
