Update on Hepatobiliary Plasticity

Abstract

The liver field has been debating for decades the contribution of the plasticity of the two epithelial compartments in the liver, hepatocytes and biliary epithelial cells (BECs), to derive each other as a repair mechanism. The hepatobiliary plasticity has been first observed in diseased human livers by the presence of biphenotypic cells expressing hepatocyte and BEC markers within bile ducts and regenerative nodules or budding from strings of proliferative BECs in septa. These observations are not surprising as hepatocytes and BECs derive from a common fetal progenitor, the hepatoblast, and, as such, they are expected to compensate for each other's loss in adults. To investigate the cell origin of regenerated cell compartments and associated molecular mechanisms, numerous murine and zebrafish models with ability to trace cell fates have been extensively developed. This short review summarizes the clinical and preclinical studies illustrating the hepatobiliary plasticity and its potential therapeutic application.

Fig. 1

Mechanisms of hepatobiliary plasticity. Mature hepatocytes and BECs are known to divide to overcome minor injuries (no plasticity, left panel ); however, when injuries are chronic or more severe, plasticity of the hepatobiliary compartment is observed (plasticity, right panel ). In this case, various options have been proposed: ( A ) Resident LPCs self-renew and differentiate into both hepatocytes and BECs, ( B ) Facultative LPCs emerge following liver injury, self-renew and differentiate as the resident LPCs do, and ( C ) mature hepatocytes and BECs transdifferentiate into each other without transitioning through a LPC stage. BECs, biliary epithelial cells; LPC, liver progenitor cell.

Fig. 2

Molecular mechanisms driving hepatobiliary plasticity. Studies in rodents and zebrafish together with observations in human specimens have revealed positive and negative molecular regulators implicated in BEC-to-hepatocytes conversion following hepatocyte injury ( A ) and in hepatocyte-to-BEC conversion following BEC injury ( B ). Factors written with capital and small letters are related to mouse and zebrafish studies, respectively. Factors with an asterisk ( * ) are related to both mouse and zebrafish studies. BEC, biliary epithelial cell.