A new study has reproduced the histological phenotype of Alagille syndrome (ALGS) using complex induced pluripotent stem cell (iPSC)-derived stem cells.
The model, presented at the European Association for the Study of the Liver (EASL) Congress in Vienna, Austria, this June, recreates the hepatic niche and aims to improve our understanding of the pathophysiology of ALGS and identify new treatment targets.
“In the liver, ALGS is characterized by bile duct paucity, cholestasis, fibrosis, as well as other heterogeneous clinical manifestations,” the authors wrote. “We developed a new 3D in vitro model of ALGS by generating liver organoids from human induced pluripotent stem cells.”
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ALGS is an autosomal dominant hereditary disease that affects multiple organs in the body and, in the liver, is characterized by bile duct paucity, cholestasis, and fibrosis.
Read more about ALGS etiology
The research team employed CRISPR/Cas9 to obtain two iPSC clones with mutations in exon 23 of JAG1, the gene associated with ALGS. From the mutated and normal iPSCs, they generated hepatic, mesenchymal, and endothelial progenitor cells that in turn created liver organoids to mimic the structure and function of the liver.
The mutated hepatic progenitor cells (HPCs) displayed a different gene expression profile from the normal HPCs, such as a reduced expression of markers associated with liver function. The mutated HPCs also showed increased expression of cytokeratin genes, found in fibrosis and cholestasis, as well as increased inflammatory markers. Furthermore, the organoids from mutated cells had an abnormal bile duct structure.
The normal HPCs formed normal bile duct structures, suggesting that the mutated versions contribute to the ALGS phenotype. The authors concluded that a useful model of ALGS can be created from liver organoids derived from mutated iPSCs, and that the model will be valuable for expanding our understanding of ALGS pathophysiology as well as identifying novel therapeutic approaches.
Reference
M’Callum MA, Selleri S, Pham T, et al. Modeling Alagille syndrome in vitro using complex induced pluripotent stem cell-derived human liver organoids. Presented at: European Association for the Study of the Liver (EASL) Congress 2023, Vienna, Austria; June 21-24. Abstract TOP-056.
