Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids

Rie Ouchi, Shodai Togo, Masaki Kimura, Tadahiro Shinozawa, Masaru Koido, Hiroyuki Koike, W. Thompson, Rebekah A. Karns, Christopher N. Mayhew, Patrick S. McGrath, Heather A. McCauley, Ran Ran Zhang, Kyle Lewis, S. Hakozaki, Autumn Ferguson, Norikazu Saiki, Yosuke Yoneyama, Ichiro Takeuchi, Yo Mabuchi, Chihiro AkazawaHiroshi Y. Yoshikawa, James M. Wells, Takanori Takebe

Research output: Contribution to journalArticlepeer-review

301 Citations (Scopus)

Abstract

Human organoid systems recapitulate in vivo organ architecture yet fail to capture complex pathologies such as inflammation and fibrosis. Here, using 11 different healthy and diseased pluripotent stem cell lines, we developed a reproducible method to derive multi-cellular human liver organoids composed of hepatocyte-, stellate-, and Kupffer-like cells that exhibit transcriptomic resemblance to in vivo-derived tissues. Under free fatty acid treatment, organoids, but not reaggregated cocultured spheroids, recapitulated key features of steatohepatitis, including steatosis, inflammation, and fibrosis phenotypes in a successive manner. Interestingly, an organoid-level biophysical readout with atomic force microscopy demonstrated that organoid stiffening reflects the fibrosis severity. Furthermore, organoids from patients with genetic dysfunction of lysosomal acid lipase phenocopied severe steatohepatitis, rescued by FXR agonism-mediated reactive oxygen species suppression. The presented key methodology and preliminary results offer a new approach for studying a personalized basis for inflammation and fibrosis in humans, thus facilitating the discovery of effective treatments. Ouchi et al. develop a reproducible method to generate multi-cellular human liver organoids from iPSCs and ESCs. The organoids recapitulate progressive features of steatohepatitis, including steatosis, inflammation, and fibrosis. A patient-derived organoid with lysosomal acid lipase deficiency exhibits the exaggerated steatohepatitis phenotype, as seen in vivo, and can be rescued by FGF19.

Original languageEnglish
Pages (from-to)374-384.e6
JournalCell Metabolism
Volume30
Issue number2
DOIs
Publication statusPublished - 06-08-2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids'. Together they form a unique fingerprint.

Cite this