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. Overall design: 37 samples, including fresh hepatocytes (Hep-1-3),fresh cholangiocytes (Chol-1-3), fresh hepatoblast (HB-1-2), Liver progenitor like cell (LPLC-1-3), fresh human hepatocytes(PHH-1-2), transplanted hepatocytes (Tx-Heps) havested from FR recipient at day 1(Tx-Hep-D1-1-4), day3 (Tx-Hep-D3-1-2), day7 (Tx-Hep-D7-1-2), Tx-Heps havested from c57 recipient at day 1(Tx-Hep(WT)-D1-1-2), Tx-Heps havested from c57 recipient preconditioned with HIR at day 1(Tx-Hep(HIR)-D1-1-5), Tx-Heps havested from FRG recipient at day 1(Tx-PHH-D1-1-5), Tx-Heps derived from Arid1a?li havested from FR recipientat day 1(Tx-Hep(Arid1aKO)-D1-1-3), and Tx-Heps derived from Arid1af/f havested from FR recipient at day 1(Tx-Hep(Arid1aWT)-D1-1-3), these animals ranged in age from 8-12w