Therapeutic liver repopulation for metabolic liver diseases: Advances from bench to bedside

Metabolic liver diseases are characterized by inherited defects in hepatic enzymes or other proteins with metabolic functions. Therapeutic liver repopulation (TLR), an approach of massive liver replacement by transplanted normal hepatocytes, could be used to provide the missing metabolic function elegantly. However, partial and transient correction of the underlying metabolic defects due to very few integrated donor cell mass remains the major obstacle for the effective and widespread use of this approach. Little engraftment and proliferation insufficiency lead to the poor outcome. This article reviews the advances in the mechanisms of initial engraftment and selective proliferation and suggests some effective treatment strategies, from pharmacological preconditioning to stem cell transplantation, to optimize liver repopulation with liver cell transplantation. Enhancing cell viability and plating efficiency, increasing sinusoidal spaces, regulation of sinusoidal endothelial cell barrier and controlling inflammatory reaction may promote initial cell engraftment. Liver‐directed irradiation, reversible portal vein embolization and fetal liver stem/progenitor cell transplantation induce preferential proliferation of donor cells substantially without severe side‐effects. Furthermore, it seems better to use combined approaches to achieve a high level of liver repopulation for the management of metabolic liver diseases.