Table 1.

Hereditary liver disease studies with organoid models

Reference	Genetic disease	Culture approach	Study highlight
Huch et al. [47], 2015	Alagille syndrome (ALGS)	ICO culture from liver biopsy	ICOs from AGS patients resemble healthy counterparts in the undifferentiated state but fail to upregulate biliary markers when differentiated to cholangiocytes. This observation corroborates with the reduced bile duct network observed in the patient’s liver.
	Alpha-1 antitrypsin (A1AT) deficiency		ICOs can also be stably propagated from tissue biopsies from A1AT deficiency patients. A1AT protein aggregates in the hepatocytes of differentiated organoids, and secreted protein is significantly reduced.
Andersson et al. [51], 2018	ALGS	ICO culture from GEMM liver biopsy	Organoids from GEMMs exhibit delayed biliary differentiation and morphogenesis and altered structural stability compared to organoids generated from wild-type mice.
Guan et al. [61], 2017	ALGS	Patient-derived iPSC	The patient’s iPSC-derived organoids can recapitulate ALGS liver pathology, including the lack of duct-like structures, diminished biliary transport, and impaired regenerative ability.
		PSC-derived hepatic organoid culture	The correction of mutation by gene editing rescues organoid functions.
Gómez-Mariano et al. [49], 2020	A1AT deficiency	ICO culture from liver biopsy	ICOs were generated from patients with heterozygous and homozygous Z (Glu342Lys) mutation on SERPINA1.
			Organoids exhibit disease phenotypes, including intracellular aggregation and lower secretion of AAT protein. The patient organoids also showed a differential response to Oncostatin-induced SERPINA1 expression.
Akbari et al. [62], 2019	Citrullinemia type 1	Patient-derived iPSC	Using the ICO culture method, authors derived an expandable Epcam-expressing hepatic organoid (eHEPO) from iPSCs.
		PSC-derived epithelial organoid culture	Differentiated eHEPOs from citrullinemia patients had a higher accumulation of ammonia and lower ureagenesis levels than eHEPOs from healthy individuals. The phenotypes were reversed with the overexpression of wild-type protein.
Nantasanti et al. [53], 2015	Wilson’s disease	Canine liver tissue biopsy	Canine liver-derived organoids exhibit similar morphology, molecular characteristics, and bipotent capacity as human ICOs.
Kruitwagen et al. [52], 2020		ICO culture	Canine Organoids with COMMD1 knockout recapitulated disease phenotypes of intracellular copper accumulation similar to Wilson disease in humans. Genetic restoration of COMMD1 expression in organoid rescues phenotype. Cells can be further engrafted into the canine liver and host survive up to two years after transplantation.
Ouchi et al. [58], 2019	Wolman disease	PSC-derived multi-tissue organoid	PSC-derived liver organoids containing both parenchymal and NPC types.
			Organoids generated from a Wolman disease patient’s iPSC exhibit pathological features observed in the liver tissue, including increased lipid accumulation and fibrosis compared to healthy controls. FGF19 treatment ameliorates disease phenotypes in the organoid.

ICO, intrahepatic cholangiocyte organoids; ALGS, Alagille syndrome; GEMM, genetically engineered mouse model; iPSC, induced pluripotent stem cell; PSC, pluripotent stem cell; NPC, non-parenchymal cell.