Hepatitis B virus infection modeling using multi-cellular organoids derived from human induced pluripotent stem cells

Chronic infection with hepatitis B virus (HBV) remains a global health concern despite the availability of vaccines. To date, the development of effective treatments has been severely hampered by the lack of reliable, reproducible, and scalable in vitro modeling systems that precisely recapitulate the virus life cycle and represent virus-host interactions. With the progressive understanding of liver organogenesis mechanisms, the development of human induced pluripotent stem cell (iPSC)-derived hepatic sources and stromal cellular compositions provides novel strategies for personalized modeling and treatment of liver disease. Further, advancements in three-dimensional culture of self-organized liver-like organoids considerably promote in vitro modeling of intact human liver tissue, in terms of both hepatic function and other physiological characteristics. Combined with our experiences in the investigation of HBV infections using liver organoids, we have summarized the advances in modeling reported thus far and discussed the limitations and ongoing challenges in the application of liver organoids, particularly those with multi-cellular components derived from human iPSCs. This review provides general guidelines for establishing clinical-grade iPSC-derived multi-cellular organoids in modeling personalized hepatitis virus infection and other liver diseases, as well as drug testing and transplantation therapy.