論文

査読有り 国際誌
2019年8月6日

Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids.

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

30
2
開始ページ
374
終了ページ
384
記述言語
英語
掲載種別
DOI
10.1016/j.cmet.2019.05.007

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.

リンク情報
DOI
https://doi.org/10.1016/j.cmet.2019.05.007
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/31155493
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687537