TABLE 1.
Studies using organoids to model liver disease
| Disease | Model | Main findings | Year | Reference |
|---|---|---|---|---|
| Alpha-1 antitrypsin deficiency (AATD) |
hiPSCs | Hepatocytes differentiated from hiPSCs from skin biopsies of AATD patients presented the accumulation of misfolded alpha-1 antitrypsin in the ER. | 2010 | Rashid et al52 |
| hiPSCs | Genetic correction of point mutation in SERPINA1 in hiPSCs using zinc finger nucleases and piggyBac technology restored the structure and function of alpha-1 antitrypsin. | 2011 | Yusa et al53 | |
| hiPSCs | Establishment of the drug screening platform using patient-derived hiPSCs; Five clinical drugs found to reduce alpha-1 antitrypsin accumulation in patient hiPSCs–derived hepatocytes; Mutation correction by transcription activator-like effector nuclease technology in patient hiPSCs–derived hepatocytes resolved alpha-1 antitrypsin accumulation. |
2013 | Choi et al54 | |
| Human liver tissue | AATD patient liver biopsy–derived organoids presented reduced ability to block elastase, ER stress, and increased apoptosis. | 2015 | Huch et al55 | |
| hiPSCs | Patient-specific hiPSCs differentiated into hepatocytes modeling individual disease phenotypes of AATD. | 2015 | Tafaleng et al56 | |
| hiPSCs | Hepatocytes differentiated from control and AATD patients’ hiPSCs used to identify the differential expression of 135 genes; hiPSC-derived hepatocytes used for toxicity prediction upon exposure to hepatotoxic drugs. |
2015 | Wilson et al57 | |
| hiPSCs | Patient-derived hiPSC hepatocytes used to explore role of JNK signaling in AATD pathophysiology. | 2017 | Pastore et al58 | |
| hiPSCs | Patient-specific hiPSC hepatocyte-like cells used to study inflammatory intermediates and unfolded protein response in AATD pathophysiology. | 2018 | Segeritz et al59 | |
| Human liver tissue | Establishment of organoids from ductal cells of human liver biopsies from controls and AATD patients; Organoids presented intracellular aggregation and lower secretion of alpha-1 antitrypsin, and lower ALB and APOB expression; Organoids treated with oncostatin M (SERPINA1 inducer) showed increased expression of alpha-1 antitrypsin transcripts. |
2020 | Gomez-Mariano et al60 | |
| hiPSCs | Establishment and characterization of a repository of AATD hiPSCs; Differentiated hepatocytes presented increased retention of alpha-1 antitrypsin; Mutation correction by CRISPR/Cas9 decreased the intracellular accumulation of alpha-1 antitrypsin in the differentiated hepatocytes. |
2020 | Kaserman et al61 | |
| hiPSCs | Using intra-splenic injections, hepatocytes differentiated from hiPSCs were transplanted into the livers of AATD transgenic mice; Transplantation induced a progressive repopulation of the mice livers without evidence of carcinogenicity. |
2021 | Chen et al62 | |
| hiPSCs | Patient-derived hiPSC hepatocytes used to evaluate alpha-1 antitrypsin-targeting compound; Tested compound blocked alpha-1 antitrypsin polymerization and increased its secretion. |
2021 | Lomas et al63 | |
| hiPSCs | Mutation correction by adenine base editing in patient-derived hiPSCs reduced ER stress and alpha-1 antitrypsin accumulation. | 2021 | Werder et al64 | |
| Alagille syndrome (ALGS) | hiPSCs | Differentiation of hiPSCs into cholangiocyte-like cells with Notch signaling deregulation. | 2015 | Sampaziotis et al42 |
| Human liver tissue | Long-term expansion of adult bile duct–derived bipotent progenitor cells from human liver; Bipotent cell-derived organoids presented duct-like phenotype that could be differentiated into hepatocyte-like in vitro and upon in vivo transplantation in mice; ALGS patient liver biopsy–derived organoids reflected ALGS phenotype with scarce biliary cells unable to integrate epithelium and undergoing apoptosis. |
2015 | Huch et al55 | |
| hiPSCs | hiPSC-hepatic organoids derived from ALGS patients presented both reduced bile duct formation and regenerative ability, as well as downregulation of Notch signaling and biliary markers; hiPSC-derived hepatic organoids genetically engineered with CRISPR/Cas9 to introduce or reverse causing mutations. |
2017 | Guan et al37 | |
| GEMM | Establishment of bile duct–derived organoids from Jag1Ndr/Ndr mice. | 2018 | Andersson et al65 | |
| Human fetal liver | Establishment of liver organoids from human fetal liver progenitor cells, recapitulating hepatobiliary organogenesis; Medium supplementation with Notch signaling inhibitor hampered bile duct maturation. |
2018 | Vyas et al66 | |
| Mouse liver | Adult mouse intrahepatic and extrahepatic duct organoids used to study Jagged/Notch signaling in the extrahepatic stem cell niche. | 2022 | Zhao et al67 | |
| Cystic fibrosis (CF) liver disease | hiPSCs | CF patient hiPSCs differentiated into functionally impaired cholangiocytes; VX-809 treatment corrected protein misfolding. |
2015 | Ogawa et al68 |
| hiPSCs | CF patient hiPSCs differentiated into cholangiocyte-like cells; VX-809 treatment increased CFTR function in vitro. |
2015 | Sampaziotis et al42 | |
| hiPSCs | Cholangiocytes differentiated from hiPSCs from healthy donors and CF patients; CF patient-derived cholangiocytes presented impaired protein kinase A/cAMP-mediated fluid secretion, increased Src-TLR4 and proinflammatory changes; Src inhibition and VX-809 treatment improved fluid secretion and cytoskeletal abnormalities. |
2018 | Fiorotto et al69 | |
| Human liver tissue | Establishment and characterization of extrahepatic and intrahepatic cholangiocyte organoids derived from human common bile duct and liver tissue; ECOs from a CF patient presented impaired CFTR channel activity. |
2020 | Verstegen et al28 | |
| Human liver tissue | Establishment of intrahepatic cholangiocytes from human tissue; Derived cholangiocytes used to assess hypoxia effect on ion secretion. |
2021 | Roos et al70 | |
| Wilson’s disease | hiPSCs | Differentiation of pluripotent hiPSCs carrying R788L mutation into hepatocyte-like cells presenting altered copper transport; In vitro phenotype rescue using self-inactivating lentiviral vector or with curcumin treatment. |
2011 | Zhang et al71 |
| Canine liver tissue | Generation of canine hepatic organoids with increased copper accumulation; Copper excretion restored upon lentiviral expression of COMMD1. |
2015 | Nantasanti et al72 | |
| Canine liver tissue | Canine hepatic COMMD1-deficient organoids with restored COMMD1 expression used for autologous transplantations through the portal vein. | 2020 | Kruitwagen et al73 | |
| Wolman disease | hiPSCs | Establishment of multicellular liver organoids derived from hiPSCs of Wolman disease patient cell lines presented increased lipid accumulation and stiffness; Organoid exposure to FGF19, simulating FXR agonism, suppressed lipid accumulation and improved cell survival. |
2019 | Ouchi et al40 |
| Glycogen storage disease type 1 |
hiPSCs | Patient-derived hiPSCs differentiated into hepatocytes presented increased intracellular glycogen accumulation. | 2010 | Rashid et al52 |
| hiPSCs | Patient-derived hiPSCs differentiated into hepatocytes recapitulating glycogen, lactate, pyruvate, and lipid accumulation. | 2013 | Satoh et al74 | |
| Citrullinemia type 1 | hiPSCs | Establishment of patient-derived hiPSCs presenting ammonia accumulation; ASS1 overexpression rescued ammonia detoxification. |
2019 | Akbari et al75 |
| Cholangiopathies | Primary human cell lines | Cholangioids established from human primary cholangiocyte cell lines from healthy and primary sclerosing cholangitis patients; Cholangioids recapitulated cellular senescence, senescence-associated secretory phenotype, and macrophage recruitment. |
2017 | Loarca et al76 |
| Bile | Bile-derived organoids established from bile of primary sclerosing cholangitis patients; Organoids expressed cholangiocyte markers and showed distinct gene expression profile when compared with bile-derived organoids from control individuals; Patient-derived organoids reacted to inflammatory stimuli from IL-17A. |
2018 | Soroka et al77 | |
| Bile | Bile-derived cholangioids established from bile of primary sclerosing cholangitis patients showed decreased TRG5 expression predisposing for more severe biliary injury; Biliary epithelial cells incubation with norUDCA restored TRG5 expression levels. |
2021 | Reich et al78 | |
| Human liver tissue | Biliary organoids derived from liver biopsies of biliary atresia patients; Biliary atresia organoids presented polarity changes, cilia misorientation, and expressed less developmental and functional markers; Biliary atresia organoids phenotype restored upon treatment with EGF and FGF2. |
2021 | Amarachintha et al79 | |
| Human liver tissue | ICOs derived from liver biopsies of primary sclerosing cholangitis patients; Necroptosis induced in patient-derived ICOs and used for necroptosis inhibitors drug screening. |
2022 | Shi et al80 | |
| hiPSCs | iPSC-derived cholangiocytes and cholangioids established from skin fibroblasts of healthy individuals and PCS patients; Patient-derived cholangioids presented disease-specific features and predisposition to cellular senescence; RNA sequencing revealed enrichment of cell cycle, senescence and fibrosis-related pathways. |
2022 | Jalan-Sakrikar et al81 | |
| Metabolic liver disease | Liver tissue | Liver organoids established from feline, mouse, dog, and human liver tissue; All organoids presented lipid accumulation upon FFA treatment. |
2017 | Kruitwagen et al82 |
| hiPSCs | Establishment of multicellular liver organoids derived from hiPSCs from healthy cell lines; Functional profiles of hepatocyte-like, stellate-like and Kupffer-like cells present in the liver organoids were evaluated; FFA-treated liver organoids presented lipid accumulation, increased lipid droplet size, hepatocyte ballooning, and increased expression of inflammatory markers, changes compatible with steatohepatitis. |
2019 | Ouchi et al40 | |
| Liver tissue | Liver organoids derived from cat liver tissue used for compound screening. | 2020 | Haaker et al83 | |
| hiPSCs | Healthy persons and patients with NASH–derived hiPSCs differentiated into hepatocytes; NASH patient–derived hepatocytes presented spontaneous lipid accumulation in the absence of FA. |
2020 | Gurevich et al84 | |
| hiPSCs hESCs |
Hepatic organoids derived from hiPSCs and hESCs presented functional hepatocyte-like cells and cholangiocyte-like cells; Organoid incubation with FFA induced lipid accumulation, lipid droplet increase, and increased ROS and lipid peroxidation, representative of NAFLD; Organoid incubation with troglitazone induced bile canaliculi decay modelling cholestasis. |
2020 | Ramli et al41 | |
| hiPSCs | Generation of liver organoids from hiPSCs using an organ-on-chip approach; Liver organoids generated in a perfusable PDMS chip and exposed to FFA; FFA exposed organoids presented lipid droplet formation, TG accumulation, increased ROS and expression of fibrogenic and proinflammatory markers. |
2020 | Wang et al85 | |
| Human liver tissue | Bipotent ductal organoids differentiated from liver tissue of patients with NASH; NASH liver organoids presented upregulated proinflammatory pathways and fibrosis markers, lipid accumulation, and increased apoptosis sensitivity. |
2021 | McCarron et al86 | |
| Alcohol-associated liver disease | Fetal liver tissue | Co-culture of hepatic organoids with human fetal liver mesenchymal cells; Upon ethanol treatment, co-cultured organoids present steatosis, fibrosis, release of inflammatory cytokines, and oxidative stress. |
2019 | Wang et al87 |
| Primary liver cancer | Human liver tissue | Liver cancer organoids derived from human tumor resection samples of HCC, CCA and CHC patients, presenting preserved histological and genetic features of original tumors; Tumor-organoids presented tumorigenic potential in xenograft models: Tumor-organoids used for drug screening of primary liver cancer-targeting compounds. |
2017 | Broutier et al29 |
| Human liver tissue | Organoids derived from human tumor needle biopsies of HCC and CCA patients, presenting morphological and expression patterns as original tumors; Sensitivity to sorafenib was evaluated in both HCC-derived and CC-derived organoids. |
2018 | Nuciforo et al30 | |
| Human liver tissue | Liver cancer organoids derived from diverse regions of surgical specimens of HCC and CCA patients, and cell lines established; Cancer organoid sensitivity tested against 129 FDA-approved drugs. |
2019 | Li et al88 | |
| Human liver tissue | Generation of CRISPR/Cas9 engineered cholangiocyte organoids to study the role of BAP1 tumor suppressor. | 2019 | Artegiani et al89 | |
| hiPSCs | HOs derived from hiPSCs genetically engineered to model initial features of human liver cancers. | 2019 | Sun et al90 | |
| Murine liver tissue | Generation of liver organoids from liver tissue of wild-type-, Kras- and p53- mutant mice; Organoids presented tumorigenic potential in xenograft mouse model, and developed tumors presented CC-compatible features; Sensitivity to gemcitabine was evaluated. |
2019 | Saborowski et al91 | |
| Viral hepatitis | hiPSCs | Functional liver organoids derived from hiPSCs and infected with HBV; HBV-infected organoids recapitulated virus life cycle and altered hepatic features. |
2018 | Nie et al92 |
| Human liver tissue | Liver organoids derived from liver specimens of healthy donors and HBV-infected patients; HBV-infected liver organoids used for drug screening; HVB-infected liver organoids presented an HCC-compatible gene signature. |
2021 | De Crignis et al93 | |
| Human liver tissue | Co-culture of CD8+T cell and liver organoids in a microfluidic chip to monitor the response to HCV. | 2022 | Natarajan et al94 | |
| SARS-CoV-2 Infection | Liver progenitor cells | Human liver ductal organoids established at infected with SARS-CoV-2 virus; Infected organoids presented downregulation of tight junctions expression and increased expression of cell death- and cellular response to external stimulus–associated genes. |
2020 | Zhao et al95 |
| Human liver tissue | Liver organoids derived from human liver biopsies and infected with SARS-Cov-2; Cholangiocyte-like cells involved in viral replication efficiency. |
2022 | Lui et al96 | |
| Human liver tissue | Liver organoids and biliary organoids derived from normal liver tissue from liver cancer patients; Organoids subjected to SARS-CoV-2 infection and liver infection route explored; Infected organoids presented the upregulation of proinflammatory cytokines and pathways. |
2022 | Zhao et al97 |
Abbreviations: AATD, Alpha-1 antitrypsin deficiency; ALGS, Alagille syndrome; CCA, cholangiocarcinoma; CF, cystic fibrosis; CHC, combined HCC/CC tumors; ECOs, extrahepatic cholangiocyte organoids; ER, endoplasmic reticulum; FA, fatty acid; FFA, free fatty acid; GEMM, genetically engineered mouse model; hESCs, human embryonic stem cells; hiPSCs, human induced pluripotent stem cell; HO, hepatocyte organoids; ICOs, intrahepatic cholangiocyte organoids; PDMS, poly dimethylsiloxane; ROS, reactive oxygen species; TG, triglycerides.