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Human liver organoids model progressive inflammatory and fibrotic injury in non-alcoholic fatty liver disease

View ORCID ProfileAnja Hess, Stefan D. Gentile, Amel Ben Saad, Raza-Ur Rahman, Tim Habboub, Alan C. Mullen
doi: https://doi.org/10.1101/2022.07.19.500693
Anja Hess
1Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
2Max Planck Institute for Molecular Genetics, Department of Genome Regulation, Berlin, Germany
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  • ORCID record for Anja Hess
Stefan D. Gentile
1Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
3Harvard Medical School, Boston, MA, USA
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Amel Ben Saad
1Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
3Harvard Medical School, Boston, MA, USA
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Raza-Ur Rahman
1Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
3Harvard Medical School, Boston, MA, USA
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Tim Habboub
1Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
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Alan C. Mullen
1Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
3Harvard Medical School, Boston, MA, USA
4Harvard Stem Cell Institute, Cambridge, MA, USA
5Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA
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  • For correspondence: acmullen@mgh.harvard.edu
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Abstract

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 Statement

A.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.

  • Abbreviations:

    HLOs
    Human liver organoids
    OS
    Orbital shaker – cultured HLOs
    ULA
    Ultra-low attachment plate – cultured HLOs
    D21
    Day 21 of differentiation
    D25
    Day 25 of differentiation
    D34
    Day 34 of differentiation
    PA
    Palmitic Acid at 500 µM
    TGF-β1
    TGF-β1 at 10 ng/µl
  • Copyright 
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    Posted July 20, 2022.
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    Human liver organoids model progressive inflammatory and fibrotic injury in non-alcoholic fatty liver disease
    Anja Hess, Stefan D. Gentile, Amel Ben Saad, Raza-Ur Rahman, Tim Habboub, Alan C. Mullen
    bioRxiv 2022.07.19.500693; doi: https://doi.org/10.1101/2022.07.19.500693
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    Human liver organoids model progressive inflammatory and fibrotic injury in non-alcoholic fatty liver disease
    Anja Hess, Stefan D. Gentile, Amel Ben Saad, Raza-Ur Rahman, Tim Habboub, Alan C. Mullen
    bioRxiv 2022.07.19.500693; doi: https://doi.org/10.1101/2022.07.19.500693

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