Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage

The liver has a remarkable capacity for regeneration after injury. Midlobular hepatocytes have been proposed as the most plastic hepatic cell type, providing definitive evidence that zone 2 of the liver lobule acts as a reservoir for hepatocyte proliferation during homeostasis and regeneration. However, the implication of other mechanisms beyond hyperplasia that contribute to liver repair have been little explored and the collaboration of another hepatocyte subpopulation has differed among previous studies depending on the model of liver injury used. Thus, re-examination of dynamics of hepatocytes during regeneration is critical to get a better understanding of underlaying mechanisms for potential cell therapy and treatment of liver diseases. Here, using a mouse model of hepatocyte- and non-hepatocyte-specific multicolor lineage tracing, we demonstrate that hepatocytes located in the midlobular region also undergo hypertrophy besides cell division in response to chemical, physical, and viral insults. Our study shows for first time that this subpopulation also combats liver impairment after infection with coronavirus. Furthermore, we demonstrate that pericentral hepatocyte subpopulation also expands in number and size during the repair process in collaboration with midlobular hepatocytes and Galectin-9-CD44 pathway may be critical for driving these processes. Interestingly, we identified transdifferentiation and cell fusion processes during liver regeneration after severe injury that may be key to recover hepatic function. Overall design: Single-cell transcriptomic profiling of liver cells from male Alb-CreERT2 Rosa26rbw mice after acute CCI4 treatment