Liver regeneration after injury: Mechanisms, cellular interactions and therapeutic innovations

Abstract

The liver possesses a distinctive capacity for regeneration within the human body. Under normal circumstances, liver cells replicate themselves to maintain liver function. Compensatory replication of healthy hepatocytes is sufficient for the regeneration after acute liver injuries. In the late stage of chronic liver damage, a large number of hepatocytes die and hepatocyte replication is blocked. Liver regeneration has more complex mechanisms, such as the transdifferentiation between cell types or hepatic progenitor cells mediated. Dysregulation of liver regeneration causes severe chronic liver disease. Gaining a more comprehensive understanding of liver regeneration mechanisms would facilitate the advancement of efficient therapeutic approaches. This review provides an overview of the signalling pathways linked to different aspects of liver regeneration in various liver diseases. Moreover, new knowledge on cellular interactions during the regenerative process is also presented. Finally, this paper explores the potential applications of new technologies, such as nanotechnology, stem cell transplantation and organoids, in liver regeneration after injury, offering fresh perspectives on treating liver disease.

Keywords: interventions; liver injury model; liver regeneration; signalling pathway.

FIGURE 1

Schematic distribution of various cells in the liver lobules.

FIGURE 2

Various factors leading to liver injury.

FIGURE 3

Signalling pathways for liver regeneration after resection. (A) Activation of MET and EGFR‐related signalling pathway activation can cause hepatocyte proliferation. (B) CCL5 binds via CCR1 and CCR5 and activates the Fox03a pathway to induce a proinflammatory Ly6C(hi) phenotype in macrophages, thereby inhibiting HGF production and delaying regenerative recovery. (C) IL‐33 binds to its receptor ST2 and induces intestinal mucosal cells to release more serotonin into the portal blood stream, activating HTR2A/p70S6K13 in hepatocytes to promote liver regeneration. (D) Cholesterol supplementation stimulates HIF‐1α and Nrf‐2 gene expression and induces hepatic inflammation and hepatocyte proliferation.

FIGURE 4

Some pathways activated in acute liver injury. OPN exacerbates APAP‐induced liver injury by increasing CYP2E1 secretion. TSP‐1 and HNF‐4α acted with Nrf2 to increase glutathione levels and attenuate APAP‐induced liver injury, respectively. DHM activated UGT1A1 and P53 to promote the associated regeneration and inhibited CYP2E1 expression to attenuate APAP‐induced liver injury.

FIGURE 5

NOTCH–YAP1/TEAD–DNMT1 axis is critical for the differentiation of LPCs/hepatocytes into BECs. When Wnt/β‐catenin signalling is enhanced, the levels of Notch ligand genes JAG1B and JAG2B are elevated in hepatocytes. Afterwards NICD can regulate downstream SOX9 and YAP1. DHMT1, a downstream effector of the YAP1–TEAD complex, directs the conversion of LPCs/hepatocytes to BECs by repressing hepatocyte‐specific genes (e.g., HNF‐4α, HNF‐1α).