Liver homeostasis is maintained by midlobular zone 2 hepatocytes

Science. 2021 Feb 26;371(6532):eabb1625. doi: 10.1126/science.abb1625.


The liver is organized into zones in which hepatocytes express different metabolic enzymes. The cells most responsible for liver repopulation and regeneration remain undefined, because fate mapping has only been performed on a few hepatocyte subsets. Here, 14 murine fate-mapping strains were used to systematically compare distinct subsets of hepatocytes. During homeostasis, cells from both periportal zone 1 and pericentral zone 3 contracted in number, whereas cells from midlobular zone 2 expanded in number. Cells within zone 2, which are sheltered from common injuries, also contributed to regeneration after pericentral and periportal injuries. Repopulation from zone 2 was driven by the insulin-like growth factor binding protein 2-mechanistic target of rapamycin-cyclin D1 (IGFBP2-mTOR-CCND1) axis. Therefore, different regions of the lobule exhibit differences in their contribution to hepatocyte turnover, and zone 2 is an important source of new hepatocytes during homeostasis and regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biliary Tract / cytology
  • Biliary Tract Diseases / physiopathology
  • Cell Proliferation
  • Cyclin D1 / metabolism
  • Gene Knock-In Techniques
  • Hepatocytes / physiology*
  • Homeostasis
  • Insulin-Like Growth Factor Binding Protein 2 / metabolism
  • Liver / cytology
  • Liver / physiology*
  • Liver Regeneration*
  • Mice
  • TOR Serine-Threonine Kinases / metabolism


  • Ccnd1 protein, mouse
  • Insulin-Like Growth Factor Binding Protein 2
  • Cyclin D1
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases