TY - JOUR T1 - A Human Multi-Lineage Hepatic Organoid Model for Liver Fibrosis JF - bioRxiv DO - 10.1101/2020.09.01.278473 SP - 2020.09.01.278473 AU - Yuan Guan AU - Annika Enejder AU - Meiyue Wang AU - Zhuoqing Fang AU - Lu Cui AU - Shih-Yu Chen AU - Jingxiao Wang AU - Yalun Tan AU - Manhong Wu AU - Xinyu Chen AU - Patrik K. Johansson AU - Issra Osman AU - Koshi Kunimoto AU - Pierre Russo AU - Sarah C. Heilshorn AU - Gary Peltz Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/09/02/2020.09.01.278473.abstract N2 - Despite its devastating consequences, liver fibrosis has no treatments. Genome engineering and a hepatic organoid system was used to produce the first in vitro model for human liver fibrosis. Hepatic organoids engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD) developed the key features of ARPKD liver pathology (abnormal bile ducts and hepatic fibrosis) in only 21 days. Second harmonic generation microscopy confirmed that the ARPKD mutation increased collagen abundance and thick collagen fiber production in hepatic organoids, which mirrored that occurring in ARPKD liver tissue. Transcriptomic and other analyses indicated that the ARPKD mutation generates cholangiocytes with increased TGFβ1 mRNA and TGFβ-associated pathway activation, which are actively involved in collagen fiber generation. The abnormal cholangiocytes promote the expansion of collagen-producing myofibroblasts with markedly increased PDGFRβ protein expression and an activated STAT3 signaling pathway. Moreover, ARPKD organoid myofibroblasts resemble those in liver tissue obtained from patients with commonly occurring forms of liver fibrosis. In addition to providing mechanistic insight into the pathogenesis of congenital and acquired forms of liver fibrosis, the anti-fibrotic efficacy of PDGFRB pathway inhibitors was demonstrated using ARPKD organoids.Competing Interest StatementThe authors have declared no competing interest.ARPKDAutosomal Recessive Polycystic Kidney DiseaseCARScoherent anti-Stokes Raman scatteringCHFcongenital hepatic fibrosisCyTOFhigh-dimensional time of flight mass cytometryDAPTN-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl esterECMextracellular matrixEMTepithelial to mesenchyme transitionFPCfibrocystin/polyductinHBhepatoblastHSCHepatic stellate cellGSEAGene signature expression analysisHOhepatic organoidHSChepatic stellate celliPSCinduced pluripotent stem cellPKHD1polycystic kidney and hepatic disease-1SAMescar associated mesenchymal cellsSHGSecond Harmonic GenerationSMAsmooth muscle actint-SNEt-Distributed Stochastic Neighbor Embedding. ER -