In the adult liver, a population of facultative progenitor cells called biliary epithelial cells (BECs) proliferate and differentiate into cholangiocytes and hepatocytes after injury, thereby restoring liver function. In mammalian models of chronic liver injury, Notch signaling is essential for bile duct formation from these cells. However, the continual proliferation of BECs and differentiation of hepatocytes in these models have limited their use for determining whether Notch signaling is required for BECs to replenish hepatocytes after injury in the mammalian liver. Here, we used a temporally restricted model of hepatic repair in which large-scale hepatocyte injury and regeneration are initiated through the acute loss of Mdm2 in hepatocytes, resulting in the rapid, coordinated proliferation of BECs. We found that transient, early activation of Notch1- and Notch3-mediated signaling and entrance into the cell cycle preceded the phenotypic expansion of BECs into hepatocytes. Notch inhibition reduced BEC proliferation, which resulted in failure of BECs to differentiate into hepatocytes, indicating that Notch-dependent expansion of BECs is essential for hepatocyte regeneration. Notch signaling increased the abundance of the insulin-like growth factor 1 receptor (IGF1R) in BECs, and activating IGFR signaling increased BEC numbers but suppressed BEC differentiation into hepatocytes. These results suggest that different signaling mechanisms control BEC expansion and hepatocyte differentiation.

在成人肝脏中，称为胆管上皮细胞（BEC）的兼性祖细胞群在损伤后增殖并分化为胆管细胞和肝细胞，从而恢复肝功能。在哺乳动物慢性肝损伤模型中，Notch 信号传导对于这些细胞形成胆管至关重要。然而，这些模型中 BEC 的持续增殖和肝细胞的分化限制了它们在确定哺乳动物肝脏损伤后 BEC 是否需要 Notch 信号来补充肝细胞方面的用途。在这里，我们使用了肝修复的时间限制模型，其中通过肝细胞中Mdm2的急性缺失启动大规模肝细胞损伤和再生，导致 BEC 快速、协调增殖。我们发现，Notch1 和 Notch3 介导的信号传导短暂、早期激活并进入细胞周期，先于 BEC 表型扩增至肝细胞中。 Notch 抑制减少了 BEC 增殖，导致 BEC 无法分化为肝细胞，表明 Notch 依赖性 BEC 扩张对于肝细胞再生至关重要。 Notch 信号传导增加了 BEC 中胰岛素样生长因子 1 受体 (IGF1R) 的丰度，激活 IGFR 信号传导增加了 BEC 数量，但抑制了 BEC 分化为肝细胞。这些结果表明不同的信号传导机制控制 BEC 扩增和肝细胞分化。