RT Journal Article
SR Electronic
T1 Human liver organoids model progressive inflammatory and fibrotic injury in non-alcoholic fatty liver disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.07.19.500693
DO 10.1101/2022.07.19.500693
A1 Anja Hess
A1 Stefan D. Gentile
A1 Amel Ben Saad
A1 Raza-Ur Rahman
A1 Tim Habboub
A1 Alan C. Mullen
YR 2022
UL http://biorxiv.org/content/early/2022/07/20/2022.07.19.500693.abstract
AB Chronic liver injury promotes inflammation, which can progress to fibrosis and cirrhosis, a major cause of mortality. Resolving the transcriptional changes orchestrating this transformation remains challenging. Here, we derive single-cell transcriptomic maps of progressive liver injury in human pluripotent stem cell (hPSC) - derived liver organoids (HLOs), modeling steatohepatitis with palmitic acid and fibrosis through TGF-β1 treatment. We observe that palmitic acid drives inflammation and non-alcoholic fatty liver disease (NAFLD) expression signatures, while TGF-β1 expands hepatic stellate-like populations, remodels cell cycle patterning, and induces extracellular matrix pathways. Analysis of receptor-ligand expression defines the induction of genes regulating Notch and fatty acid signaling with palmitic acid treatment, while the TGF-β1 response is shaped by the co-expression of COL1A1 and integrins to promote crosstalk between hepatocytes, cholangiocytes, and stellate cells. Finally, inflamed and fibrotic HLOs sequentially induce genes predicting disease progression in NAFLD. Our findings highlight HLOs as dynamic human in vitro systems to study evolving liver injury, providing a single-cell transcriptomic reference that will facilitate benchmarking future organoid-based liver injury models.Competing Interest StatementA.C.M. receives research funding from Boehringer Ingelheim, Bristol-Myers Squibb, and Glaxo Smith Klein for other projects and is also a consultant for Third Rock Ventures.HLOsHuman liver organoidsOSOrbital shaker – cultured HLOsULAUltra-low attachment plate – cultured HLOsD21Day 21 of differentiationD25Day 25 of differentiationD34Day 34 of differentiationPAPalmitic Acid at 500 µMTGF-β1TGF-β1 at 10 ng/µl