Improving the repopulation capacity of elderly human hepatocytes by decoding aging‐associated hepatocyte plasticity

Background and Aims The loss of liver regenerative capacity is the most dramatic age‐associated alteration. Because of an incomplete mechanistic understanding of the liver aging process, a successful therapeutic strategy to improve liver regeneration in the elderly has not been developed so far. Hepatocyte plasticity is a principal mechanism for producing new hepatocytes and cholangiocytes during regeneration. This study aims to promote the repopulation capacity of elderly hepatocytes by decoding the underlying mechanism about the regulation of aging on human hepatocyte plasticity. Approach and Results To understand the age‐related mechanisms, we established a hepatocyte aging model from human‐induced pluripotent stem cells and developed a method for ex vivo characterization of hepatocyte plasticity. We found that hepatocyte plasticity was gradually diminished with aging, and the impaired plasticity was caused by age‐induced histone hypoacetylation. Notably, selective inhibition of histone deacetylases could markedly restore aging‐impaired plasticity. Based on these findings, we successfully improved the plasticity of elderly primary human hepatocytes that enhanced their repopulation capacity in the liver injury model. Conclusions This study suggests that age‐induced histone hypoacetylation impairs hepatocyte plasticity, and hepatocyte plasticity might be a therapeutic target for promoting the regenerative capacity of the elderly liver.