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Cell metabolism
08 06, 2019;30 (2): 374-384.e6.

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

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
Author Information
  1. Rie Ouchi: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  2. Shodai Togo: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Department of Chemistry, Saitama University, Shimo-okubo 255, Sakura-ku, Saitama, Saitama 338-8570, Japan.
  3. Masaki Kimura: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  4. Tadahiro Shinozawa: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  5. Masaru Koido: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
  6. Hiroyuki Koike: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  7. Wendy Thompson: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  8. Rebekah A Karns: Bioinformatics Core, Cincinnati Children's Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229- 3039, USA.
  9. Christopher N Mayhew: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  10. Patrick S McGrath: Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  11. Heather A McCauley: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  12. Ran-Ran Zhang: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  13. Kyle Lewis: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  14. Shoyo Hakozaki: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  15. Autumn Ferguson: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  16. Norikazu Saiki: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
  17. Yosuke Yoneyama: Institute of Research, Division of Advanced Research, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
  18. Ichiro Takeuchi: Division of Gastroenterology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
  19. Yo Mabuchi: Department of Biochemistry and Biophysics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  20. Chihiro Akazawa: Department of Biochemistry and Biophysics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
  21. Hiroshi Y Yoshikawa: Department of Chemistry, Saitama University, Shimo-okubo 255, Sakura-ku, Saitama, Saitama 338-8570, Japan.
  22. James M Wells: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; The Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
  23. Takanori Takebe: Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan; Institute of Research, Division of Advanced Research, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; The Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. Electronic address: takanori.takebe@cchmc.org.
PMID: 31155493 DOI: 10.1016/j.cmet.2019.05.007

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.

Keywords

Wolman disease atomic force microscopy embryonic stem cell fibrosis human liver organoid induced pluripotent stem cell inflammation multicellular tissue steatohepatitis

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Grants

  1. P01 HD093363/NICHD NIH HHS
  2. P30 DK078392/NIDDK NIH HHS
  3. UG3 DK119982/NIDDK NIH HHS

MeSH Term

Cells, Cultured
Fatty Liver
Humans
Male
Models, Biological
Organoids
Pluripotent Stem Cells
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000126 (Single cell RNA-sequencing of iPS cells derived multicellular human liver organoids)

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