Transplantation-induced reprogramming determines successful hepatocyte engraftment

While demonstrated safety and efficacy in treating liver diseases, hepatocyte-based therapy faces the challenge of limited engraftment of transplanted hepatocytes (Tx-Heps) in clinical settings, akin to issues encountered in cell therapy for other solid organs. Here, we identified a conserved reprogramming state of Tx-Heps during engraftment, marked by the activation of liver progenitor genes and bipotential differentiation capacity. Transplantation reprogramming of Tx-Heps is crucial for successful engraftment, as proven by transplantation failure upon hepatocyte-specific ablation of Arid1a, which is required for Tx-Hep reprogramming. To validate translational potential, we artificially induced Tx-Hep reprogramming by in vivo treatment of either IL6 or IC7, a chimeric IL6 family protein, both of which significantly enhance hepatocyte engraftment. Our findings unveil early-stage cell fate reprogramming during transplantation and also propose a promising strategy to augment hepatocyte engraftment, which is an interesting framework to be studied in cell transplantation for other solid organs.