Precursor of chemically expanded hepatocytes (pre-cHep) with 1-million-fold expansion potential and liver repopulation capacity
Huynh, L. M.; Higuchi, Y.; Law, C. T.-Y.; Jeriha, J.; Battle, I.; Granskog, R.; Uehara, S.; Kawamura, F.; Gadd, V. L.; Man, T. Y.; Forbes, S. J.; Yusa, K.; Tsui, S. K.-W.; Suemizu, H.; Kaji, K.
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Primary human hepatocytes (PHHs) are the gold standard for toxicology and drug metabolism studies in industry. However, their limited availability, substantial batch-to-batch variability, and high cost restrict their use. Here, we report a novel culture condition that reprograms PHHs into a proliferative state. These proliferating cells, termed precursors of chemically expanded hepatocytes (pre-cHep), expand over 106-fold within 30 days while retaining liver repopulation capacity comparable to PHHs. pre-cHep can further differentiate into chemically expanded hepatocytes (cHep) as three-dimensional (3D) spheroids within 7 days in vitro, exhibiting global gene expression profiles, albumin production, and cytochrome P450 (CYP) activities similar to 3D-cultured PHH spheroids (3D PHH). Efficient genetic manipulation of pre-cHep using CRISPR/Cas9 is also achievable. Together, pre-cHep and cHep represent a promising alternative to high-quality PHHs, providing a more affordable, reproducible, and scalable source of human hepatocytes for toxicology, drug metabolism studies, disease modelling, towards precision drug development.
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