Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids
Open accessAbstract
Human organoid systems recapitulate in vivo organ architecture yet fail to capture complex pathologies such as inflammation and fibrosis. Here, using 11 different healthy and diseased pluripotent stem cell lines, we developed a reproducible method to derive multi-cellular human liver organoids composed of hepatocyte-, stellate-, and Kupffer-like cells that exhibit transcriptomic resemblance to in vivo-derived tissues. Under free fatty acid treatment, organoids, but not reaggregated cocultured spheroids, recapitulated key features of steatohepatitis, including steatosis, inflammation, and fibrosis phenotypes in a successive manner. Interestingly, an organoid-level biophysical readout with atomic force microscopy demonstrated that organoid stiffening reflects the fibrosis severity. Furthermore, organoids from patients with genetic dysfunction of lysosomal acid lipase phenocopied severe steatohepatitis, rescued by FXR agonism-mediated reactive oxygen species suppression. The presented key methodology and preliminary results offer a new approach for studying a personalized basis for inflammation and fibrosis in humans, thus facilitating the discovery of effective treatments.
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MASH organoids derived from iPSCs/ESCs display increased inflammatory and fibrotic responses and increased stiffness, all reversible with FGF19 treatment.
“These MASH organoids derived from iPSCs/ESCs display increased inflammatory and fibrotic responses in addition to increased stiffness, all of which can be reversed with fibroblast growth factor 19 (FGF19) treatment (241).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [241]
MASH organoids can be generated from iPSCs or ESCs via stepwise differentiation paralleling liver development, followed by exposure to free fatty acids.
“MASH organoids can be generated from induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs) via stepwise differentiation that parallels liver development, followed by exposure to free fatty acids (240, 241).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [241]
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- Authors
- Ouchi, R., Togo, S., Kimura, M., Shinozawa, T., Koido, M., Koike, H., Thompson, W., Karns, R. A., Mayhew, C. N., McGrath, P. S., McCauley, H. A., Zhang, R.-R., Lewis, K., Hakozaki, S., Ferguson, A., Saiki, N., Yoneyama, Y., Takeuchi, I., Mabuchi, Y., Akazawa, C., Yoshikawa, H. Y., Wells, J. M., & Takebe, T.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Yokohama City University (JP)
- University of Colorado Anschutz (US)
- Tokyo Medical and Dental University (JP)
- National Center For Child Health and Development (JP)
- Saitama University (JP)
- Corresponding author
- Takebe, Takanori
- ORCID
- Kimura, Masaki
- Shinozawa, Tadahiro
- Koido, Masaru
- Koike, Hiroyuki
- Thompson, Wendy
- Karns, Rebekah A.
- Mayhew, Christopher N.
- McGrath, Patrick S.
- McCauley, Heather A.
- Lewis, Kyle
- Ferguson, Autumn
- Saiki, Norikazu
- Yoneyama, Yosuke
- Takeuchi, Ichiro
- Mabuchi, Yo
- Akazawa, Chihiro
- Yoshikawa, Hiroshi Y.
- Wells, James M.
- Takebe, Takanori
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 30
- Issue
- 2
- Pages
- 374-384.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC6687537
- OpenAlex
- W2946842680
- Cited by
- 537
- References
- 65
- Citations by year
- 2026: 65 · 2025: 89 · 2024: 98 · 2023: 79 · 2022: 64 · 2021: 69 · 2020: 61 · 2019: 12
- FWCI
- 16.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Takeda Science Foundation
- Precursory Research for Embryonic Science and Technology (JPMJMI18CB)
- National Institutes of Health (UG3 DK119982)
- National Center for Research Resources (UL1TR001425PHS)
- New York Stem Cell Foundation
- Cincinnati Children’s Research Foundation
- Digestive Diseases Research Core Center, University of Chicago
- Japan Science and Technology Agency
- Japan Society for the Promotion of Science (JP18H02800, UG3 DK119982)
- Japan Agency for Medical Research and Development (JP18bm0704025h0001, JP18fk0210037h0001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- steatohepatitis, liver organoids, liver fibrosis, liver inflammation, steatosis, lysosomal acid lipase deficiency, reactive oxygen species, hepatocyte-like cells, hepatic stellate cells, atomic force microscopy
- MeSH terms
- Cells, Cultured, Fatty Liver, Humans, Male, Models, Biological, Organoids, Pluripotent Stem Cells
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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