A human multi-lineage hepatic organoid model for liver fibrosis

• Published in: Nature communications Vol. 12; no. 1; p. 6138
• Main Authors: Guan, Yuan, Enejder, Annika, Wang, Meiyue, Fang, Zhuoqing, Cui, Lu, Chen, Shih-Yu, Wang, Jingxiao, Tan, Yalun, Wu, Manhong, Chen, Xinyu, Johansson, Patrik K., Osman, Issra, Kunimoto, Koshi, Russo, Pierre, Heilshorn, Sarah C., Peltz, Gary
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.10.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/1; 14/63; 38; 38/39; 45/100; 631/136/1425; 692/308/1426; 692/4020/4021/1328/1325; Bile ducts; Collagen; Congenital diseases; Fibers; Fibrosis; Genetic disorders; Humanities and Social Sciences; Kidney diseases; Kidneys; Liver; multidisciplinary; Mutation; Organoids; Pathogenesis; Pathology; Polycystic kidney; Science; Science (multidisciplinary); Signal transduction; Stat3 protein; Transcriptomes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26410-9

To investigate the pathogenesis of a congenital form of hepatic fibrosis, human hepatic organoids were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD). Here we show that these hepatic organoids develop the key features of ARPKD liver pathology (abnormal bile ducts and fibrosis) in only 21 days. The ARPKD mutation increases collagen abundance and thick collagen fiber production in hepatic organoids, which mirrors ARPKD liver tissue pathology. Transcriptomic and other analyses indicate that the ARPKD mutation generates cholangiocytes with increased TGFβ pathway activation, which are actively involved stimulating myofibroblasts to form collagen fibers. There is also an expansion of collagen-producing myofibroblasts with markedly increased PDGFRB protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resemble those present in commonly occurring forms of liver fibrosis. PDGFRB pathway involvement was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. Besides providing insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies. Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder which is associated with kidney and liver pathology, including liver fibrosis. Here the authors develop and characterize human liver organoids with a ARPKD mutation, and find that they show aspects of the pathology, including fibrosis.