Triggering Mechanisms of Hepatocyte Repopulation during Liver Regeneration

Liver regeneration is a complex process involving hepatocyte proliferation and differentiation, which is essential for restoring liver function after liver injury. Hepatocyte repopulation plays a central role in this regenerative process, and extensive research has aimed to elucidate the triggering mechanisms of hepatocyte proliferation as well as the origins of new hepatocytes. Partial hepatectomy, drug-induced liver injuries, and other genetic mouse models have been widely employed to investigate the regenerative machinery of the liver. However, the exact sources of regenerating hepatocytes remain controversial. While substantial evidence supports the model in which pre-existing hepatocytes self-duplicate to replenish the liver, alternative hypotheses suggest that biliary epithelial cells and hepatic progenitor cells also contribute under certain injury conditions. Recently, advanced techniques, including lineage tracing and spatial transcriptomics, have been utilized to track cell lineages and analyze changes in cell composition during liver regeneration, greatly advancing the field. Given that hepatocytes perform the majority of liver functions, understanding the contributing signaling pathways of hepatocyte repopulation is the most critical among the whole process of liver regeneration. Therefore, this review specifically focuses on summarizing current findings in the cellular and molecular mechanisms underlying hepatocyte repopulation during liver regeneration.