Hepatobiliary Organoids and Their Applications for Studies of Liver Health and Disease: Are We There Yet?

Organoid culture systems have emerged as a frontier technology in liver and biliary research. These three-dimensional (3D) cell cultures derived from pluripotent and adult hepatobiliary cells model organ structure and function. Building on gastrointestinal organoid establishment, hepatobiliary organoid cultures were generated from mouse leucine-rich repeat-containing G-protein-coupled receptor 5-positive liver progenitor cells. Subsequently, 3D hepatobiliary organoid cultures were developed from hepatocytes and cholangiocytes to model human and animal hepatobiliary health and disease. Hepatocyte organoids have been used to study Alagille syndrome, fatty liver disease, Wilson disease, hepatitis B viral infection, and cystic fibrosis. Cholangiocyte organoids have been established to study normal cholangiocyte biology and primary sclerosing cholangitis and to test organoid potential to form bile ducts and gallbladder tissue in vitro. Hepatobiliary cancer organoids, termed tumoroids, have been established from frozen and fresh human tissues and used as a drug-testing platform and for biobanking of cancer samples. CRISPR-based gene modifications and organoid exposure to infectious agents have permitted the generation of organoid models of carcinogenesis. This review summarizes currently available adult cell-derived hepatobiliary organoid models and their applications. Challenges faced by this young technology will be discussed, including the cellular immaturity of organoid-derived hepatocytes, co-culture development to better model complex tissue structure, the imperfection of extracellular matrices, and the absence of standardized protocols and model validation.