TY - JOUR
T1 - Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids
AU - Ouchi, Rie
AU - Togo, Shodai
AU - Kimura, Masaki
AU - Shinozawa, Tadahiro
AU - Koido, Masaru
AU - Koike, Hiroyuki
AU - Thompson, W.
AU - Karns, Rebekah A.
AU - Mayhew, Christopher N.
AU - McGrath, Patrick S.
AU - McCauley, Heather A.
AU - Zhang, Ran Ran
AU - Lewis, Kyle
AU - Hakozaki, S.
AU - Ferguson, Autumn
AU - Saiki, Norikazu
AU - Yoneyama, Yosuke
AU - Takeuchi, Ichiro
AU - Mabuchi, Yo
AU - Akazawa, Chihiro
AU - Yoshikawa, Hiroshi Y.
AU - Wells, James M.
AU - Takebe, Takanori
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/8/6
Y1 - 2019/8/6
N2 - 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.
AB - 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.
KW - Wolman disease
KW - atomic force microscopy
KW - embryonic stem cell
KW - fibrosis
KW - human liver organoid
KW - induced pluripotent stem cell
KW - inflammation
KW - multicellular tissue
KW - steatohepatitis
UR - http://www.scopus.com/inward/record.url?scp=85068540376&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068540376&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2019.05.007
DO - 10.1016/j.cmet.2019.05.007
M3 - Article
C2 - 31155493
AN - SCOPUS:85068540376
SN - 1550-4131
VL - 30
SP - 374-384.e6
JO - Cell Metabolism
JF - Cell Metabolism
IS - 2
ER -