Generation and applications of an expandable and mature hiPSC-derived liver organoid

Organoids have emerged as a powerful tool for modeling liver diseases, drug screening, and personalized treatments. However, they have a limited capacity to generate functional hepatocytes in a reproducible and efficient manner. Here, we designed a novel method to efficiently and reproducibly establish a protocol for generating functionally mature SB-HEOs (SB431542/BMP4-hepatic endoderm organoids) from hiPSC-derived hepatic endoderm (HE) cells. The maturation of these organoids was confirmed through transcriptome analysis and functional expression detection. We extended this culture system to various biomedical applications. This system can be used to identify hepatotoxicity with DILI drugs, model disease using OA stress, metabolize drugs using liquid chromatography-tandem mass spectrometry, and repopulate FRG mice. These organoids have both expansion and maturation characteristics, high drug metabolism ability to prolong the survival of FRG mice, can accurately identify hepatotoxic and non-hepatotoxic drugs, and mimic metabolic dysfunction-associated steatotic liver disease. Thus, SB-HEO provide a new cellular system for toxicology testing, drug metabolism, modeling liver diseases, and regenerative medicine. Especially benefiting from the high expression of CYP450 activity, SB-HEO shows high potential in the fields of drug testing and regenerative medicine.