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Modeling fatty liver disease and progression with stem cell derived hepatocytes
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  • Published: 07 January 2026

Modeling fatty liver disease and progression with stem cell derived hepatocytes

  • Yao Wang1,2,
  • David Berlin1,2,
  • Yong Li3,
  • Lok Man Ko1,
  • Zhenzhu Qi1,
  • Jiayi Feng4,
  • Christopher T. Clark1,2,
  • Diandian Cheng1,2,
  • Melisa Andrade1,2,
  • Eric Potma3 &
  • …
  • Quinton Smith1,2,4,5 

Scientific Reports , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cell biology
  • Diseases
  • Gastroenterology
  • Stem cells

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most pervasive liver disorders. It can progress to metabolic dysfunction-associated steatohepatitis (MASH), hallmarked by increased inflammation and inclination to permanent liver damage. Given the limited treatment options available to patients, models that recapitulate critical features of disease pathogenesis are needed to improve drug development. Here, a MASLD model was developed by differentiating hepatocyte-like cells (HLCs) from human induced pluripotent stem cells (hiPSCs) in 2D and 3D, in which hepatic aggregates exhibited enhanced functionality. Induced HLCs exposed to free fatty acids led to a steatotic phenotype, partially reducing hepatic function. Biochemical cues released from induced HLCs promoted activation of fibroblasts, resulting in increased inflammatory cytokine secretion and extracellular matrix (ECM) deposition. These findings suggest paracrine signaling from hepatocytes to the surrounding stroma can trigger the progression of MASH and fibrosis. Collectively, our results demonstrate the utility of hiPSC derivatives for modeling liver diseases and reveal how heterotypic interactions can drive disease progression.

Data availability

All data generated in this study to demonstrate the key findings are provided in the manuscript and the Supplementary Information. Any other data supporting this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr. Edwin Monuki for kindly providing the KOLF iPSC line.

Funding

The California Institute for Regenerative Medicine supported research reported in this publication under Award Number EDUC4-12822 to Y.W. and M.A. The content is solely the responsibility of the authors and does not necessarily represent the official views of the California Institute for Regenerative Medicine. This study was made possible in part through access to the Optical Biology Core Facility of the Developmental Biology Center, a shared resource supported by the Cancer Center Support Grant (CA-62203) and NIH-S10OD032327-01. Q.S. acknowledges the support from the National Institutes of Health (NIH) (Grant No. R35GM151099) and the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute (Grant No. GT15187).

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, University of California, Irvine, Irvine, CA, 92697, USA

    Yao Wang, David Berlin, Lok Man Ko, Zhenzhu Qi, Christopher T. Clark, Diandian Cheng, Melisa Andrade & Quinton Smith

  2. Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, 92697, USA

    Yao Wang, David Berlin, Christopher T. Clark, Diandian Cheng, Melisa Andrade & Quinton Smith

  3. Department of Chemistry, University of California, Irvine, Irvine, CA, 92697, USA

    Yong Li & Eric Potma

  4. Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, 92697, USA

    Jiayi Feng & Quinton Smith

  5. Department of Materials Science and Engineering, University of California, Irvine, Irvine, CA, 92697, USA

    Quinton Smith

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Contributions

Y.W. designed the study, performed most of the experiments, analyzed data, and wrote the manuscript. Y.L. performed the experiments, analyzed the data, and wrote the manuscript on Raman spectroscopy and imaging. D.B., L.M.K, Z.Q., J.F., C.T.C., D.C., and M.A. supported the conduct of select experiments. D.B. partook in the processing of confocal images. M.A. supported the study design. E.P. designed and supervised the study regarding Raman spectroscopy and imaging. Q.S. led the design and execution of the study and wrote the manuscript.

Corresponding author

Correspondence to Quinton Smith.

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Wang, Y., Berlin, D., Li, Y. et al. Modeling fatty liver disease and progression with stem cell derived hepatocytes. Sci Rep (2026). https://doi.org/10.1038/s41598-025-34762-1

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  • Received: 22 October 2025

  • Accepted: 31 December 2025

  • Published: 07 January 2026

  • DOI: https://doi.org/10.1038/s41598-025-34762-1

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