TABLE 1.
Summary of liver organoids modeling noncancer liver diseases
| Modeled disease | Species source(s) | Cell sources | Culture system | Modeled phenotypes | References |
|---|---|---|---|---|---|
| Alagille syndrome | Human | Liver biopsies from 3 AGS patients | Matrigel | Failure to upregulate biliary makers (CK19 and CK7); Inability to integrate into epithelium; Increased apoptosis in the organoid lumen |
13 |
| Alagille syndrome | Mouse | Bile duct fragment from JAG1 Ndr/Ndr mice | Matrigel | Disrupted bile duct morphogenesis and delayed differentiation | 34 |
| Alpha-1 antitrypsin deficiency | Human | Liver biopsies from AATD patients | Matrigel | A1AT protein aggregation, reduced A1AT protein secretion, and increased apoptosis within the differentiated organoids; Reduced ability of supernatants from differentiated organoids to block elastase activity |
13 |
| Alpha-1 antitrypsin deficiency | Human | Liver biopsies from ZZ, MZ AATD patients | Matrigel | Intracellular aggregation and lower secretion of A1AT protein; Lower expression of albumin and apolipoprotein B |
35 |
| Wilson disease | Canine | iPSCs from COMMD1-deficient dog models | Matrigel | Higher intracellular copper accumulation | 36,37 |
| Wilson disease | Human | Intrahepatic cholangiocytes from patients with Wilson disease | Matrigel | Increased sensitivity to copper treatment | 38 |
| Ornithine transcarbamylase deficiency | Human | iPSCs from a OTCD patient | Matrigel | Reduced urea cycle activity | 39 |
| Cystic fibrosis–associated liver disease | Human | iPSCs from CF patients | Matrigel | Formation of branched ductal structures and impaired FIS | 40 |
| Cystic fibrosis–associated liver disease | Human | iPSCs from a CF patient | Matrigel | Loss of function to regulate intracellular chloride concentration | 41 |
| Cystic fibrosis–associated liver disease | Human | Intrahepatic cholangiocytes from CF patients | Matrigel | Impaired FIS | 38 |
| Wolman disease | Human | iPSCs from Wolman disease patients | Matrigel | Prominent steatosis and fibrosis | 42 |
| Polycystic liver disease | Human | iPSCs from a PLD patient | Matrigel | Increased organoid size responsive to secretin and decreased organoid size responsive to octreotide and somatostatin | 41 |
| Biliary atresia | Human | Liver biopsies from BA patients | Matrigel | Lack of basal positioning nucleus, misorientation of cilia, and lower expression of ZO-1; Lower expression of developmental and functional markers; Increased permeability; Aberrant expression of F-actin, β-catenin, and Ezrin |
43 |
| Biliary atresia | Human | EPCAM+ cells from liver biopsies of BA patients | Matrigel | Aberrant morphology and apical-basal organization; Beta-amyloid deposition around bile duct |
44 |
| Biliary atresia | Mouse | Murine neonatal extrahepatic cholangiocytes | Collagen-Matrigel mixture | Disrupted cellular polarity and increased permeability of biliary epithelium | 45 |
| Biliary atresia | Human | Fetal liver, adult liver, and bile duct | Matrigel | Morphological changes consistent with BA | 46 |
| Methylmalonic acidemia | Human | Intrahepatic cholangiocytes from MMA patients | Matrigel | Increased propionylcarnitine concentration compared with controls | 38 |
| Alcohol-associated liver disease | Human | EtOH-treated hFLMC/hEHO | Matrigel | Enhanced oxidative stress; Responsive injury and fibrogenesis to EtOH treatment; Upregulation of genes encoding the lipogenic-associated enzymes and transcription factors |
47 |
| NAFLD | Feline | FFA-treated liver organoids derived from ASCs | Matrigel | Increased intracellular lipid accumulation; Upregulation of PLIN2, CPT1A, and PPARG |
48,49 |
| NAFLD | Human | FFA-treated liver organoids derived from PSCs | Matrigel | Increased intracellular lipid accumulation; Increased metabolites regarding lipid metabolism; Enriched gene sets for fatty acid metabolism |
3 |
| NAFLD | Human | Oleic acid-treated liver organoids derived from healthy and diseased PSCs | Matrigel | Increased intracellular lipid accumulation; Enlarged cells size and hepatocyte ballooning; Overexpression of inflammatory cytokines |
42 |
| NAFLD | Human | Lactate, pyruvate, and octanoic acid-treated liver organoids derived from intrahepatic cholangiocytes | Matrigel | Increased intracellular lipid accumulation, triglyceride, diacylglycerol, and glucose level; Distinct mitochondrial impairment |
2 |
| NASH | Mouse | Liver organoids derived from MCD diet-induced NASH mice models | Matrigel | Upregulation of collagen I and α-SMA; Occurrence of EMT |
50 |
| NASH | Human | Liver organoids derived from liver tissue of NASH patients | Matrigel | Increased intracellular lipid accumulation | 51 |
| Hepatitis B | Human | iPSCs | Microwell culture system | Upregulation of HBV infection-promoting factors, including NTCP, glypican 5, PPARA, and CEBPA; Permissiveness of HBV infection and progeny HBV propagation; Hepatic dysfunction after HBV infection |
52 |
| Hepatitis B | Human | Differentiated liver progenitor-like cells | Matrigel | Expression of host factors essential to HBV entry and replication, including NTCP, RXRA, and HNF4A; Permissive of HBV infection |
53 |
| Hepatitis B | Human | ASCs from HBV-infected patients | Matrigel | Expression of NTCP; Permissiveness for HBV infection and replication, and progeny HBV propagation |
54 |
| Hepatitis C | Human | iPSC-derived hepatic progenitors | Inverted colloid crystal scaffold | Expression of proteins responsible for HCVcc entry and HCV packaging; Permissiveness for genotype 2a HCV reporter virus infection |
55 |
| Hepatitis E | Human | ASCs from human adult and fetal liver | Matrigel | Permissiveness for HEV infection and replication; Activation of innate defense; Positive response to recombinant IFN-α |
56 |
| COVID-19 | Human | Human PSC-derived adult hepatocyte and cholangiocyte. | Matrigel | Expression of ACE2; Permissiveness for SARS-CoV-2 infection; Upregulation of chemokines and relative inflammatory pathways similar as primary pulmonary autopsy samples from patients with COVID-19 |
57 |
| COVID-19 | Human | Bile duct–derived progenitor cells | Matrigel | Expression of ACE2 and TMPPSS2; Significant cholangiocyte tropism of SARS-CoV-2 infection; Disrupted cholangiocyte barrier and bile acid transportation |
58 |
| Hepatic Plasmodium infection | Human and simian | Primary hepatocytes | Macroporous cellusponge | Expression of CD81; Maturation of schizonts and hypnozoites of Plasmodium cynomolgi and Plasmodium vivax into blood-invasive merosomes |
59 |
| Drug-induced liver injury | Human | iPSCs and ESCs | Matrigel | Higher expression and induction rate of CYP450 enzymes (CYP3A4, 1A2, 2C9); Hepatic injury caused by APAP |
60 |
| Drug-induced liver injury | human | iPSCs | Perfusable chip system | Higher expression and induction rate of CYP450 enzymes (CYP3A4, 2C9, 2B6); Hepatic injury caused by APAP |
61 |
| Drug-induced liver injury | Human | iPSCs and ESCs | Matrigel | Higher expression of CYP450 enzymes (CYP3A4, 1A2, 2A6, 2E1); Hepatic injury caused by APAP, trovafloxacin, and troglitazone |
3 |
| Drug-induced liver injury | Human | iPSCs and ESCs | 384-well based high-speed live imaging platform | Expression of CYP450 enzymes (CYP3A4, 1A2, 2C9, 7A1); Hepatic response to 283 drugs |
62 |
| Drug-induced liver fibrosis | Human | HepaRG cell line and iPSC-derived HSCs | Matrigel | Expression of CYP450 enzyme (CYP3A4); APAP-induced HSC activation, collagen secretion, and deposition |
63 |
| Drug-induced phospholipidosis | Human | ASCs | Matrigel | Expression of CYP450 enzyme (CYP3A4); Upregulation of LAMP2 and presentation of characteristic lamellar bodies with exposure to amiodarone, sertraline, and amikacin |
64 |
| Primary sclerosing cholangitis | Human | Cholangiocytes from patients with primary sclerosing cholangitis | Matrigel | Cellular senescence and macrophage accumulation; Smaller size and slower growth rate compared with normal controls; Lack of central lumens |
65 |
| Primary sclerosing cholangitis | Human | Cholangiocytes from bile, common bile duct, and liver explant of patients with primary sclerosing cholangitis | Matrigel | Primary sclerosing cholangitis-related autoimmune dysregulation | 20 |
| Primary sclerosing cholangitis | Human | Cholangiocytes from bile of patients with primary sclerosing cholangitis | Matrigel | Reactive immune phenotypes under inflammatory stimuli | 21 |
| Hyperuricemia | Human | Primary human hepatocyte from paracarcinomatous liver tissue | Matrigel | Higher uric acid level in the supernatant of HUA organoids; Sensitive to allopurinol |
66,67 |
Abbreviations: A1AT, alpha-1 antitrypsin; AATD, alpha-1 antitrypsin deficiency; ACE2, angiotensin I converting enzyme 2; AGS, Alagille syndrome; APAP, acetaminophen; ASC, adult stem cell; BA, Biliary atresia; CEBPA, CCAAT/enhancer-binding protein alpha; CF, cystic fibrosis; CFLD, cystic fibrosis–associated liver disease; CK, cytokeratin; COMMD1, copper metabolism domain containing 1; CPT1A, carnitine palmitoyl transferase 1A; CYP, cytochrome; EMT, epithelial-mesenchymal transition; EPCAM, epithelial cell adhesion molecule; ESC, embryonic stem cell; EtOH, ethanol; FFA, free fatty acid; FIS, forskolin-induced swelling; HCVcc, cell cultured HCV; hFLMC/hEHO, human fetal mesenchymal cells/human ESC-derived hepatic organoids; HNF4A, hepatocyte nuclear factor 4 alpha; HUA, hyperuricemia; IFN-α, interferon-alpha; iPSC, induced pluripotent stem cells; JAG1, jagged1; LAMP2, lysosome-associated membrane protein 2; MCD, methionine deficient and choline deficient; MDS, mitochondrial DNA depletion syndrome; MMA, methylmalonic acidemia; NTCP, sodium-taurocholate cotransporting polypeptide; OTCD, ornithine transcarbamylase deficiency; PLD, polycystic liver disease; PLIN2, perilipin 2; PPARA, peroxisome proliferator-activated receptor alpha; PPARG, peroxisome proliferator-activated receptor gamma; RXRA, retinoid X receptor A; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPPSS2, transmembrane serine protease 2; ZO-1, zona occludens-1; α-SMA, alpha-smooth muscle actin.