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

Abstract

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.

Organoids: The current status and biomedical applications

“…166 Human liver organoids have emerged as advanced tools for studying hepatitis virus infection and several laboratories have generated liver organoids infected by hepatitis B, C, and E viruses. [167][168][169][170][171] Recent research indicated that when liver organoids derived from healthy donors were cocultured with the recombinant virus or the serum of patients with HBVs, the organoids were infected, and the virus proliferated actively. 172 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen of coronavirus disease 2019 (COVID-19), which usually causes moderate respiratory disease such as fever and cough, and even acute respiratory syndrome.…”

Induced Pluripotent Stem Cell-Derived Organoids: Their Implication in COVID-19 Modeling

“…In the last few years, liver organoid differentiation methods have advanced rapidly, enabling the generation of 3D-bioprinted liver organoids or liver-on-a-chip [ 111 , 112 , 113 ]. To date, liver organoids have been successfully used to model various diseases affecting liver tissue and screen novel drug candidates [ 114 , 115 , 116 ]; therefore, it was not surprising that the research community reached out to them at the beginning of the pandemic to examine pathological processes in the liver caused by SARS-CoV-2 [ 105 , 106 , 117 ].…”

Engineering Organoids for in vitro Modeling of Phenylketonuria

“…With the development of CRISPR-Cas tools, gene editing of mammalian cells has become accessible ( Cong et al, 2013 ; Mali et al, 2013 ). One of the most straightforward PKU-related targets that may be interrogated using gene editing approaches include PAH knock-out or mutations in a liver organoid model ( Cao et al, 2021 ). We can also modulate and analyze other PKU-related targets.…”