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Home  > Press Release  > Modeling Steatohepatitis in Human with Pluripotent Stem Cell-Derived Organoids

Modeling Steatohepatitis in Human with Pluripotent Stem Cell-Derived Organoids

Highlights

iPSCs and ESCs generate reproducible multi-cellular human liver organoids
Free fatty acid exposure induces the steatohepatitis phenotype in organoids
Measuring organoid stiffness reflects fibrosis severity
FGF19 alleviates the steatohepatitis phenotype of Wolman disease-derived organoids

Summary

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.

Journal Article

JOURNAL:
Cell Metabolism

TITLE:
Modeling Steatohepatitis in Human with Pluripotent Stem Cell-Derived Organoids

DOI:
https://doi.org/10.1016/j.cmet.2019.05.007

Correspondence to

Takanori TAKEBE, Professor
Institute of Research, Division of Advanced Research
Tokyo Medical and Dental University(TMDU)
E-mail:ttakebe.ior(at)tmd.ac.jp


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