Liver progenitor cell-driven liver regeneration

Abstract

The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver diseases. Hepatocyte-driven liver regeneration that involves the proliferation of preexisting hepatocytes is a primary regeneration mode. On the other hand, liver progenitor cell (LPC)-driven liver regeneration that involves dedifferentiation of biliary epithelial cells or hepatocytes into LPCs, LPC proliferation, and subsequent differentiation of LPCs into hepatocytes is a secondary mode. This secondary mode plays a significant role in liver regeneration when the primary mode does not effectively work, as observed in severe liver injury settings. Thus, promoting LPC-driven liver regeneration may be clinically beneficial to patients with severe liver diseases. In this review, we describe the current understanding of LPC-driven liver regeneration by exploring current knowledge on the activation, origin, and roles of LPCs during regeneration. We also describe animal models used to study LPC-driven liver regeneration, given their potential to further deepen our understanding of the regeneration process. This understanding will eventually contribute to developing strategies to promote LPC-driven liver regeneration in patients with severe liver diseases.

Fig. 1. The structure of the liver in mammals and zebrafish.

The liver consists of hepatocytes, BECs, Kupffer cells, HSCs, and endothelial cells. LPCs are thought to arise near bile ductules, also known as the canals of Hering, which are positioned between the bile duct and hepatocytes. In the zebrafish liver, most BECs make up bile ductules.

Fig. 2. Origins of LPCs.

BECs and hepatocytes can give rise to LPCs in various liver injury settings. HSCs might be an additional source of LPCs in certain liver injury settings.

Fig. 3. The beneficial and negative roles of LPCs.

LPCs play a beneficial role in liver regeneration/recovery by differentiating themselves into hepatocytes, whereas they play negative roles by contributing to liver fibrosis and tumor formation, such as HCC and ICC.