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 personalized basis for inflammation and fibrosis
in human, thus facilitating the discovery of effective treatments. Ouchi et al. develop
a reproducible method to generate multi-cellular human liver organoids from iPSC/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.