Contributions of new hepatocyte lineages to liver growth, maintenance, and regeneration in mice

Abstract

The contributions that de novo differentiation of new hepatocyte lineages makes to normal liver physiology are unknown. In this study, a system that uniquely marks cells during a finite period following primary activation of a serum albumin gene promoter/enhancer-driven Cre recombinase (albCre) transgene was used to investigate birthrates of new hepatocyte lineages from albumin (Alb)-naive precursors in mice. Elapsed time was measured with a two-color fluorescent marker gene that converts from expressing tandem dimer Tomato (tdT; a red fluorescent protein) to expressing green fluorescent protein (GFP) following primary exposure to Cre. The accumulation of GFP and the decay of tdT each contributed to a regular fluorescence transition, which was calibrated in vivo. In normal adults, this system revealed that a steady-state level of 0.076% of all hepatocytes had differentiated within the previous 4 days from albCre-naive cell lineages. In comparison with resting adult livers, the relative abundance of these newborn hepatocytes was elevated 3.7-fold in the growing livers of juveniles and 8.6-fold during liver regeneration after partial hepatectomy in adults.

Conclusion: Newborn hepatocyte lineages arising from Alb-naive cells contribute to liver maintenance under normal conditions. Hepatocyte lineage birthrates can vary in response to the liver's physiological status.