A human multi-lineage hepatic organoid model for liver fibrosis

Yuan Guan, Annika Enejder, Meiyue Wang, Zhuoqing Fang, Lu Cui, Shih-Yu Chen, Jingxiao Wang, Yalun Tan, Manhong Wu, Xinyu Chen, Patrik K. Johansson, Issra Osman, Koshi Kunimoto, Pierre Russo, Sarah C. Heilshorn and Gary Peltz ()
Additional contact information
Yuan Guan: Department of Anesthesiology, Pain and Perioperative Medicine
Annika Enejder: Stanford University
Meiyue Wang: Department of Anesthesiology, Pain and Perioperative Medicine
Zhuoqing Fang: Department of Anesthesiology, Pain and Perioperative Medicine
Lu Cui: Institute of Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford University School of Medicine
Shih-Yu Chen: Shih-Yu Chen, Institute of Biomedical Sciences, Academia Sinica
Jingxiao Wang: Department of Anesthesiology, Pain and Perioperative Medicine
Yalun Tan: Department of Anesthesiology, Pain and Perioperative Medicine
Manhong Wu: Department of Anesthesiology, Pain and Perioperative Medicine
Xinyu Chen: Department of Anesthesiology, Pain and Perioperative Medicine
Patrik K. Johansson: Stanford University
Issra Osman: Department of Anesthesiology, Pain and Perioperative Medicine
Koshi Kunimoto: Institute of Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford University School of Medicine
Pierre Russo: Perelman School of Medicine at The University of Pennsylvania
Sarah C. Heilshorn: Stanford University
Gary Peltz: Department of Anesthesiology, Pain and Perioperative Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26410-9

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