Sublethal executioner caspase activation in hepatocytes promotes liver regeneration through the JAK/STAT3 pathway

Apoptosis has been reported to drive regeneration in many species. Executioner caspases, the key effectors in apoptosis, are responsible for production and secretion of various pro-regenerative signals from apoptotic cells to the surrounding cells. However, whether executioner caspase activation (ECA) can promote regeneration without inducing apoptosis is poorly understood. Here, by generating transgenic mice carrying a lineage tracing system for cells that have experienced ECA, we demonstrate that ECA occurs in a few hepatocytes in homeostatic livers. The fraction of hepatocytes with ECA dramatically expands during regeneration after partial hepatectomy (PHx) or carbon tetrachloride (CCl4) treatment. Interestingly, rather than undergoing apoptosis, the majority of hepatocytes with ECA survive and proliferate during liver regeneration. Inhibition of ECA in livers results in reduced hepatocyte proliferation and impaired regeneration, whereas increasing ECA to a level sufficient to kill hepatocytes also impedes regeneration, suggesting that ECA needs to be precisely controlled at a sublethal level. Mechanistically, we show that ECA promotes hepatocyte proliferation through enhancing JAK/STAT3 activity. Our work reveals an essential apoptosis-independent role of executioner caspases in liver regeneration.