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IL22 supports Long-Term Expansion of Mouse and Human Hepatocytes in vitro.

ABSTRACT: Hepatocytes have wide applications in drug development, disease modeling, and cell therapy. However, to expand hepatocytes in large quantities in vitro without losing their functions remains a challenging task. Here 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 ~1025 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. Collectively, this study provides a simple culture system enables large-scale expansion of both mice and human hepatocytes in vitro, and elucidates the critical pathways and TFs involved in these processes.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE290952 | GEO | 2025/03/06

REPOSITORIES: GEO

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