RNA-seq transcriptional profiling in IL22 induced mouse and human hepatocytes in vitro, IL22 induced WT and STAT3 knock-out hepatocytes in vitro, Bhlha15 and Arntl2 induced hepatocytes in vitro.

We report that IL22, a cytokine highly upregulated after partial hepatectomy or hepatocyte transplantation, could support long-term expansion (>30 passages, with theoretical expansion of ~1030 times within ~150 days) of mice hepatocytes in vitro by dedifferentiate hepatocytes into hepatocyte progenitor cells (HPCs), which maintain the capacity of differentiation into mature hepatocytes. With transcriptomic analysis and lineage-specific deletion, we uncover the critical involvement of STAT3 pathway in IL22-mediated hepatocyte to HPC conversion. Two key transcription factors (TFs) down-stream of STAT3 pathway, Bhlha15 and Arntl2, govern IL22-induced hepatic dedifferentiation. Expression of these two TFs directly initiates the dedifferentiation of hepatocytes into HPCs, which could be expanded in long-term without the supplement of IL22. IL22 also supports human hepatocyte growth in simple culture condition. Within 30 days, human hepatocytes could be expanded by more than 10,000-fold by dedifferentiation into HPCs, which maintain the full capacity of maturation.