New research provides insights into hepatocyte renewal during maintenance and repair, with the identification of a subset of hepatocytes expressing telomerase (TERTHigh hepatocytes) that can repopulate the liver during homeostasis and after injury.

Understanding the mechanisms of liver regeneration has been an intense area of research, particularly with respect to the cellular sources that maintain and repair the liver. Existing evidence linked telomerase to long-term renewal in stem cells, and germline inactivating mutations in telomerase genes have been shown to predispose mice and humans to liver cirrhosis. Given these observations, Lin et al. reasoned that telomerase expressed in liver cells could have unique properties and wanted to characterize this particular subset of cells.

Using a series of experiments in mice (including lineage tracing analysis), the researchers identified TERTHigh hepatocytes throughout the liver, representing 3–5% of hepatocytes. Crucially, during homeostasis, they found that this subset of liver cells could repopulate the liver, comprising ~30% of the liver at 1 year. Moreover, these TERTHigh hepatocytes were distributed throughout all lobular zones (the majority located in the periportal and midlobular areas), and yielded expanding hepatocyte clones by a self-renewal and differentiation mechanism.

After chemical injury (a single dose of carbon tetrachloride damaging the liver periportal zone), repopulation by TERTHigh hepatocytes was accelerated and their progeny could cross zonal boundaries during repair. Furthermore, these cells contributed to hepatocyte regeneration after diet-induced liver injury, and genetic ablation of TERTHigh cells combined with diet-induced injury resulted in a marked increase in hepatic stellate cell activation and liver fibrosis in the mice.

The authors propose a ‘distributed model’ to explain hepatocyte renewal. “According to this model, rare TERTHigh hepatocytes located throughout the lobule form enlarging clones during homeostasis in response to hepatocyte loss, and this response is accelerated during liver injury,” they write.