Journal
EBIOMEDICINE
Volume 35, Issue -, Pages 114-123Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2018.08.014
Keywords
Liver organoid; hiPSC; Hepatitis B virus; Virus-host interactions
Funding
- JST Research Center Network for Realization of Regenerative Medicine [17bm0304002h0105]
- Japan Agency for Medical Research and Development [17fk0310103j0001]
- Japan Society for the Promotion of Scienc KAKENHI [18F18101]
- JSPS International Fellowships for Research in Japan [P18101]
- Austrian Science Fund (FWF) [P18101] Funding Source: Austrian Science Fund (FWF)
- Grants-in-Aid for Scientific Research [18F18101] Funding Source: KAKEN
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Therapies against hepatitis B virus (HBV) have improved in recent decades; however, the development of individualized treatments has been limited by the lack of individualized infection models. In this study, we used human induced pluripotent stem cell (hiPSC) to generate a functional liver organoid (ID) that inherited the genetic background of the donor, and evaluated its application in modeling HBV infection and exploring virus-host interactions. To establish a functional hiPSC-LO, we cultured hiPSC-derived endodermal, mesenchymal, and endothelial cells with a chemically defined medium in a three-dimensional microwell culture system. Based on cell-cell interactions, these cells could organize themselves and gradually differentiate into a functional organoid, which exhibited stronger hepatic functions than hiPSC derived hepatic like cell (HLC). Moreover, the functional LO demonstrated more susceptibility to HBV infection than hiPSC-HLC. and could maintain HBV propagation and produce infectious virus for a prolonged duration. Furthermore, we found that virus infection could cause hepatic dysfunction of hiPSC-LOs, with down-regulation of hepatic gene expression, induced release of early acute liver failure markers, and altered hepatic ultrastructure. Therefore, our study demonstrated that HBV infection in hiPSC-LOs could recapitulate virus life cycle and virus induced hepatic dysfunction, suggesting that hiPSC-LOs may provide a promising individualized infection model for the development of individualized treatment for hepatitis. (C) 2018 The Authors. Published by Elsevier B.V.
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