Research ArticleRegeneration

Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion and inhibits hepatocyte differentiation

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Science Signaling  22 Jun 2021:
Vol. 14, Issue 688, eaay9185
DOI: 10.1126/scisignal.aay9185

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Notching up proliferation

Liver injury triggers the proliferation of biliary epithelial cells (BECs), which can give rise to cholangiocytes or hepatocytes, two major cell types in the liver. Using a model of acute, genetically driven liver injury, Minnis-Lyons et al. found that Notch signaling was required for the injury-induced proliferation of BECs because it sensitized the cells to insulin-like growth factor 1 (IGF1). Although treating mice with IGF1 after liver injury increased BEC proliferation, it did not boost hepatocyte numbers, demonstrating that additional signals are required to specify the hepatocyte fate in BECs. These findings suggest that therapeutic interventions that increase BEC proliferation may not be sufficient to stimulate tissue repair in patients with liver disease.


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.

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