Liver progenitor cells regulate ductular reaction and induce fibrosis upon severe liver injury via RAGE signaling

The origin and role of liver progenitor cells (LPCs) also known as atypical biliary epithelial-like cells have been a controversial topic from their involvement in regeneration during liver damage to being associated with severe liver disease progression, fibrosis and tumor initiation. Enhanced proliferation of LPCs, called the ductular reaction, leads to portal fibrogenesis - characterized by stellate cell activation, ECM deposition, inflammation. The receptor for advanced glycation end products (RAGE) signaling axis is often associated with this chronic inflammation-associated tissue damage and plays an essential role in modulating the tumor microenvironment. RAGE mediates the LPC expansion, onset of liver fibrosis and HCC formation. LPC expansion, commonly manifests as a “Ductular reaction (DR) ” in chronic liver disorder.

To investigate if RAGE also drives the ductular reaction in cholestatic (bile acid) mediated liver injury, we investigated CDE-diet induced ductular reactions in a mouse model with LPC-specific RAGE knockout and labelled LPCs. Ablation of RAGE in LPCs strongly impaired ductular reaction. Strikingly, this was accompanied in vivo by reduction of activated hepatic stellate cells that populate in the liver as response to fibrosis. In vitro transcriptomic studies of isolated primary LPCs stimulated with supernatants from necrotic hepatocytes showed that stress response, inflammatory and pro-fibrotic pathways were enriched in LPCs upon treatment with necrotic medium. Most interestingly, signaling pathways that regulate organ size, tissue homeostasis and cell survival pathways were found to be RAGE-dependent. Clusters of stem cell renewal-related genes were deregulated upon ablation of RAGE. In line with the whole transcriptome profile, we demonstrated that ablation of RAGE attenuates LPCs organoid-forming ability, implying that RAGE regulates stemness properties of LPCs.

Our recent results demonstrated that RAGE is required for LPCs activation and proliferation, as well as the crosstalk with stellate cells in supporting fibrogenesis. Taken together, our data uncover a potential mechanistic insight on the role of RAGE in LPCs in association with fibrosis upon chronic liver injury.

Keywords: ECM-Extracellular matrix, CDE- Choline-deficient-ethionine

Publication History

Article published online:
04 January 2021