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NOV 14, 2018 3:00 PM PST

Modeling Inflammation and Fibrosis in Humans with PSC-derived Steatohepatitis Liver Organoids

Speaker
  • Associate Director, CuSTOM, Professor and Assistant Professor, Cincinnati Children's Hospital Tokyo Medical and Dental University Yokohama City University, Principal Investigator, Takeda-CiRA
    Biography
      Dr. Takebe is an Associate Director of Center for Stem Cell and Organoid Medicine (CuSTOM) at the Cincinnati Children's Hospital Medical Center and Professor at Yokohama City University, and Tokyo Medical and Dental University, Japan. He serves as Board of Directors at International Society of Stem Cell Research (ISSCR). His lab investigates the mechanisms of human organogenesis, and develops mini-organ technologies from human stem cells - namely organ bud based approaches. He is applying iPSC-liver buds into drug discovery study as well as transplant application - for patients with a rare congenital metabolic disorder, ultimately expanding the clinical indications to diseases like liver cirrhosis.

    Abstract

    Human organoid systems recapitulate in vivo organ architecture, yet fail to capture complex pathologies such as inflammation and fibrosis. Here we developed multi-cellular human liver organoids (HLO) from 11 different healthy and diseased PSC lines that display essential features of steatohepatitis. Single-cell-level analysis revealed steatohepatitis organoids exhibited persistent hepatic steatosis, followed by progressive activation of pro-inflammatory and fibrotic lineages. Interestingly, expression of the steatohepatitis phenotype correlates with the presence of clinically significant GWAS factors: PNPLA3, GCKR and TM6SF2. We developed an organoid-level readout with atomic force microscopy, and demonstrated that organoid stiffening reflects the fibrosis severity. Furthermore, organoid model of an iatrogenic parental nutrition associated liver disease (PNALD) identified obeticholic acid as effective in preventing pathology progression, suggesting the potential repurposing for PNALD. The presented key methodology and preliminary results offer a new method for studying human precision for inflammation and fibrosis, facilitating the discovery of effective treatments.


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