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Abstract
Hepatocyte proliferation is the principal mechanism for generating new hepatocytes
in liver homeostasis and regeneration. Recent studies have suggested that this ability
is not equally distributed among hepatocytes but concentrated in a small subset of
hepatocytes acting like stem cells, located around the central vein or distributed
throughout the liver lobule and exhibiting active WNT signaling or high telomerase
activity, respectively. These findings were obtained by utilizing components of these
growth regulators as markers for genetic lineage tracing. Here, we used random lineage
tracing to localize and quantify clonal expansion of hepatocytes in normal and injured
liver. We found that modest proliferation of hepatocytes distributed throughout the
lobule maintains the hepatocyte mass and that most hepatocytes proliferate to regenerate
it, with diploidy providing a growth advantage over polyploidy. These results show
that the ability to proliferate is broadly distributed among hepatocytes rather than
limited to a rare stem cell-like population. Chen et al. investigate potential differences
in how much hepatocytes in the different zones of the liver lobule contribute to hepatocyte
replacement in normal and injured liver. They find that, in principle, location and
extent of hepatocyte proliferation are broadly distributed, with specific effects
of type of injury and ploidy.