Original Articles: Viral Hepatitis

A multicellular liver organoid model for investigating hepatitis C virus infection and nonalcoholic fatty liver disease progression

Lee, Jaeseo1; Gil, Dayeon2,3; Park, Hyeyeon2,3; Lee, Youngsun2,3; Mun, Seon Ju1; Shin, Yongbo1,4; Jo, Eunji5; Windisch, Marc P.5; Kim, Jung-Hyun2,3,6; Son, Myung Jin1,4,7

Author Information

1Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea

2Korea National Stem Cell Bank, Chungcheongbuk-do, Republic of Korea

3Department of Chronic Diseases Convergence Research, Division of Intractable Diseases Research, Korea National Institute of Health, Osong Health Technology Administration Complex, Republic of Korea

4Department of Functional Genomics, Korea University of Science & Technology (UST), Daejeon, Republic of Korea

5Applied Molecular Virology Laboratory, Institute Pasteur Korea, Seongnam-si, Republic of Korea

6College of Pharmacy, Ajou University, Suwon, Republic of Korea

7School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea

Abbreviations: ACTA, actin alpha 2; ALB, albumin; CCL, C-C motif chemokine ligand; COL1A1, collagen type Ⅰ alpha 1 chain; COL3A1, collagen type Ⅲ alpha 1 chain; dpi, days postinfection; ESC, embryonic stem cell; FA, fatty acid; iMAC, induced macrophage; Kp-LO, Kupffer-like cell-containing liver organoid; LO, liver organoid; LO + iMAC, iMAC cocultured liver organoid; MARCO, macrophage receptor with collagenous structure; PLIN2, perilipin 2; PPAR, peroxisome proliferator-activated receptor; scRNA-seq, single-cell RNA sequencing; SREBF, sterol regulatory element binding factor; VCL, vinculin; VSIG4, v-set and immunoglobulin domain-containing 4.

Jaeseo Lee and Dayeon Gil contributed equally to this work.

Correspondence Jung-Hyun Kim, College of Pharmacy, Ajou University, Suwon, 16499, Republic of Korea. Email: [email protected] Myung Jin Son, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea. Email: [email protected]

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s website, www.hepjournal.com.

Hepatology 80(1):p 186-201, July 2024. | DOI: 10.1097/HEP.0000000000000683
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Abstract

Background and Aims: 

HCV infection can be successfully managed with antiviral therapies; however, progression to chronic liver disease states, including NAFLD, is common. There is currently no reliable in vitro model for investigating host-viral interactions underlying the link between HCV and NAFLD; although liver organoids (LOs) show promise, they currently lack nonparenchymal cells, which are key to modeling disease progression.

Approach and Results: 

Here, we present a novel, multicellular LO model using a coculture system of macrophages and LOs differentiated from the same human pluripotent stem cells (PSCs). The cocultured macrophages shifted toward a Kupffer-like cell type, the liver-resident macrophages present in vivo, providing a suitable model for investigating NAFLD pathogenesis. With this multicellular Kupffer-like cell-containing LO model, we found that HCV infection led to lipid accumulation in LOs by upregulating host lipogenesis, which was more marked with macrophage coculture. Reciprocally, long-term treatment of LOs with fatty acids upregulated HCV amplification and promoted inflammation and fibrosis. Notably, in our Kupffer-like cell-containing LO model, the effects of 3 drugs for NASH that have reached phase 3 clinical trials exhibited consistent results with the clinical outcomes.

Conclusions: 

Taken together, we introduced a multicellular LO model consisting of hepatocytes, Kupffer-like cells, and HSCs, which recapitulated host-virus intercommunication and intercellular interactions. With this novel model, we present a physiologically relevant system for the investigation of NAFLD progression in patients with HCV.

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