Role of liver progenitors in acute liver injury

Abstract

Acute liver failure (ALF) results from the acute and rapid loss of hepatocyte function and frequently exhibits a fulminant course, characterized by high mortality in the absence of immediate state-of-the-art intensive care and/or emergency liver transplantation (ELT). The role of hepatocyte-mediated liver regeneration during acute and chronic liver injury has been extensively investigated, and recent studies suggest that hepatocytes are not exclusively responsible for the regeneration of the injured liver during fulminant liver injury. Liver progenitor cells (LPC) (or resident liver stem cells) are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. This review aims to provide an overview of the role of the LPC population during ALF, and the role of putative cytokines, growth factors, mitogens, and hormones in the LPC response. We will highlight the potential interaction among cellular compartments during ALF, and discuss the possible prognostic value of the LPC response on ALF outcomes.

Keywords: acute liver failure; hepatic failure; liver progenitor cells; liver regeneration; oval cells; severe acute liver injury; stem cells.

Figure 1

During acute liver injury, hepatocyte (and cholangiocyte) apoptosis, and necrosis occur. With minor injury, restoration of hepatocyte mass and function is mediated by the replication of remaining healthy hepatocytes (and cholangiocytes). During a major insult, massive, and confluent hepatocyte loss occurs. There are insufficient healthy remaining hepatocytes mass to restore hepatic function; as such, the liver progenitor (LPC) or liver stem cell compartment is activated in an attempt to restore epithelial cell mass, architecture, and function. The bipotential LPCs reside in the Canals of Herring (CoH), located in the niche of the biliary-hepatocytic interface, and are able to infiltrate along the liver plate and differentiate into hepatocytes and cholangiocytes. LPCs are surrounded by epithelial cells, non-parenchymal cells such as hepatic stellate cells, as well as immune cells and extracellular matrix. These regenerative processes are triggered and regulated by the plethora of cytokines, growth factors and metabolic signals. Resurrection of morphogenic signals (i.e., Hedgehog, Wnt, Notch) also occurs, particularly during massive injury, to invoke the liver progenitor cell compartment. In brief, these molecules act in concert to ensure that sufficient regeneration occurs, and yet, not exceed normal homeostatic requirements.