Increased proliferation of hepatic periportal ductal progenitor cells contributes to persistent hypermetabolism after...

Prolonged and persistent hypermetabolism and excessive inflammatory response after severe trauma is detrimental and associated with poor outcome. The predisposing pathology or signals mediating this complex response are essentially unknown. As the liver is the central organ mediating the systemic metabolic responses and considering that adult hepatic stem cells are on top of the hierarchy of cell differentiation and may pass epigenetic information to their progeny, we asked whether liver progenitor cells are activated, signal hypermetabolism upon post-traumatic cellular stress responses, and pass this to differentiated progeny. We generated Sox9CreER^T2 : ROSA26 EYFP mice to lineage-trace the periportal ductal progenitor cells (PDPCs) and verify the fate of these cells post-burn. We observed increased proliferation of PDPCs and their progeny peaking around two weeks post-burn, concomitant with the hepatomegaly and the cellular stress responses. We then sorted out PDPCs, PDPC-derived hepatocytes and mature hepatocytes, compared their transcriptome and showed that PDPCs and their progeny present a significant up-regulation in signalling pathways associated with inflammation and metabolic activation, contributing to persistent hypermetabolic and hyper-inflammatory state. Furthermore, concomitant down-regulation of LXR signalling in PDPCs and their progeny implicates the therapeutic potential of early and short-term administration of LXR agonists in ameliorating such persistent hypermetabolism.