Liver homeostasis is maintained by midlobular zone 2 hepatocytes

Area of Science:

• Hepatology
• Cell Biology
• Regenerative Medicine

Background:

• The liver lobule is zoned, with hepatocytes expressing diverse metabolic enzymes.
• The specific hepatocyte subsets responsible for liver repopulation and regeneration are not fully understood.
• Previous fate-mapping studies have examined only limited hepatocyte populations.

Purpose of the Study:

• To systematically compare the contribution of distinct hepatocyte subsets to liver homeostasis and regeneration.
• To identify the cellular origins of hepatocytes during normal turnover and after injury.

Main Methods:

• Utilized 14 distinct murine fate-mapping strains.
• Systematically analyzed hepatocyte subset behavior during homeostasis and regeneration.
• Investigated the molecular pathways driving repopulation from specific zones.

Main Results:

• During homeostasis, zone 1 and zone 3 hepatocytes decreased, while zone 2 hepatocytes increased.
• Zone 2 hepatocytes, sheltered from injury, contributed significantly to regeneration after both pericentral and periportal damage.
• Repopulation from zone 2 was mediated by the insulin-like growth factor binding protein 2-mechanistic target of rapamycin-cyclin D1 (IGFBP2-mTOR-CCND1) axis.

Conclusions:

• Different regions of the liver lobule exhibit distinct contributions to hepatocyte turnover.
• Zone 2 hepatocytes represent a crucial source for new hepatocytes during both homeostasis and liver regeneration.
• The IGFBP2-mTOR-CCND1 axis is a key driver of zone 2 hepatocyte-mediated liver repopulation.