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ResearchIn-Press PreviewHepatology Open Access | 10.1172/jci.insight.187099

Live Cell Imaging of Human Liver Fibrosis using Hepatic Micro-Organoids

Yuan Guan,1 Zhuoqing Fang,1 Angelina Hu,1 Sarah Roberts,1 Meiyue Wang,1 Wenlong Ren,1 Patrik K. Johansson,2 Sarah C. Heilshorn,2 Annika Enejder,2 and Gary Peltz1

1Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, United States of America

2Department of Materials Science and Engineering, Stanford University, Stanford, United States of America

3Department of Materials Science and Engineering, Stanford University, Stanford, Canada

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1Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, United States of America

2Department of Materials Science and Engineering, Stanford University, Stanford, United States of America

3Department of Materials Science and Engineering, Stanford University, Stanford, Canada

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1Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, United States of America

2Department of Materials Science and Engineering, Stanford University, Stanford, United States of America

3Department of Materials Science and Engineering, Stanford University, Stanford, Canada

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1Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, United States of America

2Department of Materials Science and Engineering, Stanford University, Stanford, United States of America

3Department of Materials Science and Engineering, Stanford University, Stanford, Canada

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1Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, United States of America

2Department of Materials Science and Engineering, Stanford University, Stanford, United States of America

3Department of Materials Science and Engineering, Stanford University, Stanford, Canada

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1Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, United States of America

2Department of Materials Science and Engineering, Stanford University, Stanford, United States of America

3Department of Materials Science and Engineering, Stanford University, Stanford, Canada

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1Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, United States of America

2Department of Materials Science and Engineering, Stanford University, Stanford, United States of America

3Department of Materials Science and Engineering, Stanford University, Stanford, Canada

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1Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, United States of America

2Department of Materials Science and Engineering, Stanford University, Stanford, United States of America

3Department of Materials Science and Engineering, Stanford University, Stanford, Canada

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1Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, United States of America

2Department of Materials Science and Engineering, Stanford University, Stanford, United States of America

3Department of Materials Science and Engineering, Stanford University, Stanford, Canada

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1Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, United States of America

2Department of Materials Science and Engineering, Stanford University, Stanford, United States of America

3Department of Materials Science and Engineering, Stanford University, Stanford, Canada

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Published December 10, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.187099.
Copyright © 2024, Guan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 10, 2024 - Version history
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Abstract

Due to the limitations of available in vitro systems and animal models, we lack a detailed understanding of the pathogenetic mechanisms and have minimal treatment options for liver fibrosis. Therefore, we engineered a live cell imaging system that assesses fibrosis in a human multi-lineage hepatic organoid in a microwell (i.e., microHOs). Transcriptomic analysis revealed that TGFβ1 converted mesenchymal cells in microHOs into myofibroblast-like cells resembling those in fibrotic human liver tissue. When pro-fibrotic intracellular signaling pathways were examined, the anti-fibrotic effect of receptor-specific tyrosine kinase inhibitors was limited to the fibrosis induced by the corresponding growth factor, which indicates their anti-fibrotic efficacy would be limited to fibrotic diseases solely mediated by that growth factor. Based upon transcriptomic and transcription factor activation analyses in microHOs, GSK3β and p38 MAPK inhibitors were identified as potential new broad-spectrum therapies for liver fibrosis. Other new therapies could subsequently be identified using the microHO system.

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