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

Abstract

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.

Biliverdin reductase B impairs cholangiocarcinoma cell motility by inhibiting the Notch/Snail signaling pathway

“…Activation of the Notch pathway leads to the release of the NICD from the cell membrane, which, upon nuclear translocation, converts RBPJ from a repressor to an activator of transcription via the recruitment of additional coactivators. In the liver, Notch signaling is essential for biliary fate and morphogenesis [42][43][44][45]. Despite the wealth of data suggesting a role for Notch in CCA, little evidence exists to support a causative role for Notch in tumor initiation in human CCA.…”

Abnormal respiratory progenitors in fibrotic lung injury

“…It is assumed that the severity of the injury determines the degree that ATII cells derived from airway progenitors can be replenished. Consistently, in other organs, ductal epithelial cells can contribute to functional unit progenitor cell regeneration, such as β cell in pancreas [ 22 ] and hepatocytes in liver [ 23 ].…”

Cellular Therapies in Pediatric Liver Diseases

“…Although utilizing HTx for the treatment of ALF appears promising, it requires hepatocytes to be transplanted into an extremely harsh environment containing high levels of cellular necrosis and apoptosis [ 15 ]. As such, novel approaches are being examined to overcome this harsh microenvironment including implanting cells in alternative sites such as the peritoneum [ 16 ] and lymph nodes [ 17 ].…”