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Cited by 164Liver physiology and pathologyTissue Engineering and Regenerative Medicine3D Printing in Biomedical Research

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Organoids to model liver disease

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Nuciforo, Sandro, Heim, Markus H.·2021·JHEP Reports
DOI 10.1016/j.jhepr.2020.100198PMC PMC7672322
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Abstract

The organoid model represents a major breakthrough in cell biology that has revolutionised biomedical research. Organoids are 3D physiological in vitro structures that recapitulate morphological and functional features of in vivo tissues and offer significant advantages over traditional cell culture methods. Liver organoids are of particular interest because of the pleiotropy of functions exerted by the human liver, their utility to model different liver diseases, and their potential application as cell-based therapies in regenerative medicine. Moreover, because they can be derived from patient tissues, organoid models offer new perspectives in personalised medicine and drug discovery. In this review, we discuss the current liver organoid models for the study of liver disease.

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Fig. 1 Workflow for the generation of liver-derived organoids. Liver organoids can be derived from different sources such as adult liver tissue, foetal liver tissue, bile and pluripotent stem cells. Adult- and foetal liver tissue-derived progenitor cells can be stimulated to form organoids of the hepatocyte (hep-org) or cholangiocyte (chol-org) lineage following incubation with a defined combination of growth factors.23,24,27,28 Foetal liver-derived progenitors/hepatoblasts can give rise to both hep-orgs and chol-orgs.29 Progenitor cells isolated from bile can be grown as chol-orgs. Hep-orgs can be partially transdifferentiated into chol-orgs, but not vice-versa. However, chol-orgs can undergo differentiation into hepatocyte- or cholangiocyte-like cells according to Huch and colleagues (not shown).23,24 Pluripotent stem cells of embryonic (ESC) or somatic (iPSC) origin first require a 3-stage differentiation protocol to generate hepatoblast-like cells (depicted here the protocol according to Sampaziotis et al.25), that are subsequently embedded in extracellular matrix to promote 3D growth and organoid formation. BMP, bone morphogenetic protein; EGF, epidermal growth factor; ESC, embryonic stem cell; FGF, fibroblast growth factor; GSK3-i, glycogen synthase kinase 3 inhibitor; HGF, hepatocyte growth factor; iPSC, induced pluripotent stem cell; PI3K-i, phosphoinositide 3 kinase inhibitor; RA, retinoic acid; TGFα, transforming growth factor alpha; TGFBR1-i, transforming growth factor beta receptor 1 inhibitor.
Fig. 1 Workflow for the generation of liver-derived organoids. Liver organoids can be derived from different sources such as adult liver tissue, foetal liver tissue, bile and pluripotent stem cells. Adult- and foetal liver tissue-derived progenitor cells can be stimulated to form organoids of the hepatocyte (hep-org) or cholangiocyte (chol-org) lineage following incubation with a defined combination of growth factors.23,24,27,28 Foetal liver-derived progenitors/hepatoblasts can give rise to both hep-orgs and chol-orgs.29 Progenitor cells isolated from bile can be grown as chol-orgs. Hep-orgs can be partially transdifferentiated into chol-orgs, but not vice-versa. However, chol-orgs can undergo differentiation into hepatocyte- or cholangiocyte-like cells according to Huch and colleagues (not shown).23,24 Pluripotent stem cells of embryonic (ESC) or somatic (iPSC) origin first require a 3-stage differentiation protocol to generate hepatoblast-like cells (depicted here the protocol according to Sampaziotis et al.25), that are subsequently embedded in extracellular matrix to promote 3D growth and organoid formation. BMP, bone morphogenetic protein; EGF, epidermal growth factor; ESC, embryonic stem cell; FGF, fibroblast growth factor; GSK3-i, glycogen synthase kinase 3 inhibitor; HGF, hepatocyte growth factor; iPSC, induced pluripotent stem cell; PI3K-i, phosphoinositide 3 kinase inhibitor; RA, retinoic acid; TGFα, transforming growth factor alpha; TGFBR1-i, transforming growth factor beta receptor 1 inhibitor.CC BY · PubMed Central
Fig. 2 Workflow for the generation of liver cancer organoids. Liver cancer organoids can be directly established from patient tumour tissue collected after surgical resection or needle biopsy. The generation of cancer organoids follows the same protocol as described for normal liver organoids. Alternatively, liver cancer organoids can also be established from healthy chol-orgs using CRISPR/Cas9-mediated genetic engineering for the precise introduction of cancer driver mutations. Murine liver tumours derived from mouse models of chemical carcinogenesis can be used for the generation of murine liver cancer organoids. Genetically engineered mouse models carrying floxed oncogenes and/or tumour suppressors can be used to generate a flexible system based on conditionally mutant chol-orgs. CCA, cholangiocellular carcinoma; CHC, combined hepato-cholangiocarcinoma; CRISPR/Cas9, clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9; GEMM, genetically engineered mouse model; HCC, hepatocellular carcinoma.
Fig. 2 Workflow for the generation of liver cancer organoids. Liver cancer organoids can be directly established from patient tumour tissue collected after surgical resection or needle biopsy. The generation of cancer organoids follows the same protocol as described for normal liver organoids. Alternatively, liver cancer organoids can also be established from healthy chol-orgs using CRISPR/Cas9-mediated genetic engineering for the precise introduction of cancer driver mutations. Murine liver tumours derived from mouse models of chemical carcinogenesis can be used for the generation of murine liver cancer organoids. Genetically engineered mouse models carrying floxed oncogenes and/or tumour suppressors can be used to generate a flexible system based on conditionally mutant chol-orgs. CCA, cholangiocellular carcinoma; CHC, combined hepato-cholangiocarcinoma; CRISPR/Cas9, clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9; GEMM, genetically engineered mouse model; HCC, hepatocellular carcinoma.CC BY · PubMed Central
Fig. 3 Translational applications of liver-derived organoid models. Patient-derived organoid biobanks are important resources for applications in academic research and drug development. Organoid models of liver disease can be directly generated from diseased donors or alternatively from healthy donors following CRISPR/Cas9-mediated insertion of disease-causing mutations, e.g. for the study of monogenic liver diseases or liver cancer. Organoid-based drug discovery allows for a more physiological assessment of drug sensitivity and hepatotoxicity, facilitating the selection of potent drugs with a safe profile. PDOs could support clinicians during the therapeutic decision-making process by predicting the efficacy of different treatments for the same indication. Finally, organoid-based cell therapies represent an alternative to liver transplantation for various diseases, in particular monogenic liver diseases that can be corrected with genome editing methods. CRISPR/Cas9, clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9; DILI, drug-induced liver injury; PDO, patient-derived organoid.
Fig. 3 Translational applications of liver-derived organoid models. Patient-derived organoid biobanks are important resources for applications in academic research and drug development. Organoid models of liver disease can be directly generated from diseased donors or alternatively from healthy donors following CRISPR/Cas9-mediated insertion of disease-causing mutations, e.g. for the study of monogenic liver diseases or liver cancer. Organoid-based drug discovery allows for a more physiological assessment of drug sensitivity and hepatotoxicity, facilitating the selection of potent drugs with a safe profile. PDOs could support clinicians during the therapeutic decision-making process by predicting the efficacy of different treatments for the same indication. Finally, organoid-based cell therapies represent an alternative to liver transplantation for various diseases, in particular monogenic liver diseases that can be corrected with genome editing methods. CRISPR/Cas9, clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9; DILI, drug-induced liver injury; PDO, patient-derived organoid.CC BY · PubMed Central
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Metadata

Authors
Nuciforo, S., & Heim, M. H.
Affiliations
University of Basel (CH)
Corresponding author
Heim, Markus H.
ORCID
Venue
JHEP Reports
Publisher
Elsevier BV
Published
2021-02
Volume
3
Issue
1
Pages
100198
ISSN
2589-5559 (ISSN-L)
DOI
10.1016/j.jhepr.2020.100198
PMC
PMC7672322
OpenAlex
W3094299399
Cited by
164
References
106
Citations by year
2026: 16 · 2025: 30 · 2024: 40 · 2023: 31 · 2022: 27 · 2021: 19
FWCI
2.57
Type
journal article
Language
en
Open access
Licence
Locations
  • JHEP Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • SystemsX.ch
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • European Research Council
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
Keywords
liver organoids, liver disease modeling, organoid culture, regenerative medicine, cell therapy, personalized medicine, drug discovery, patient-derived tissue

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