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Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology

Author

Listed:
  • Ingmar Mederacke

    (College of Physicians and Surgeons, Columbia University)

  • Christine C. Hsu

    (College of Physicians and Surgeons, Columbia University)

  • Juliane S. Troeger

    (College of Physicians and Surgeons, Columbia University)

  • Peter Huebener

    (College of Physicians and Surgeons, Columbia University)

  • Xueru Mu

    (College of Physicians and Surgeons, Columbia University)

  • Dianne H. Dapito

    (Institute of Human Nutrition, Columbia University)

  • Jean-Philippe Pradere

    (College of Physicians and Surgeons, Columbia University)

  • Robert F. Schwabe

    (College of Physicians and Surgeons, Columbia University
    Institute of Human Nutrition, Columbia University)

Abstract

Although organ fibrosis causes significant morbidity and mortality in chronic diseases, the lack of detailed knowledge about specific cellular contributors mediating fibrogenesis hampers the design of effective antifibrotic therapies. Different cellular sources, including tissue-resident and bone marrow-derived fibroblasts, pericytes and epithelial cells, have been suggested to give rise to myofibroblasts, but their relative contributions remain controversial, with profound differences between organs and different diseases. Here we employ a novel Cre-transgenic mouse that marks 99% of hepatic stellate cells (HSCs), a liver-specific pericyte population, to demonstrate that HSCs give rise to 82–96% of myofibroblasts in models of toxic, cholestatic and fatty liver disease. Moreover, we exclude that HSCs function as facultative epithelial progenitor cells in the injured liver. On the basis these findings, HSCs should be considered the primary cellular target for antifibrotic therapies across all types of liver disease.

Suggested Citation

  • Ingmar Mederacke & Christine C. Hsu & Juliane S. Troeger & Peter Huebener & Xueru Mu & Dianne H. Dapito & Jean-Philippe Pradere & Robert F. Schwabe, 2013. "Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3823
    DOI: 10.1038/ncomms3823
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    Cited by:

    1. Lu Han & Yongxia Wu & Kun Fang & Sean Sweeney & Ulyss K. Roesner & Melodie Parrish & Khushbu Patel & Tom Walter & Julia Piermattei & Anthony Trimboli & Julia Lefler & Cynthia D. Timmers & Xue-Zhong Yu, 2023. "The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Yuan Guan & Annika Enejder & Meiyue Wang & Zhuoqing Fang & Lu Cui & Shih-Yu Chen & Jingxiao Wang & Yalun Tan & Manhong Wu & Xinyu Chen & Patrik K. Johansson & Issra Osman & Koshi Kunimoto & Pierre Rus, 2021. "A human multi-lineage hepatic organoid model for liver fibrosis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Haushabhau S. Pagire & Suvarna H. Pagire & Byung-kwan Jeong & Won-Il Choi & Chang Joo Oh & Chae Won Lim & Minhee Kim & Jihyeon Yoon & Seong Soon Kim & Myung Ae Bae & Jae-Han Jeon & Sungmin Song & Hee , 2024. "Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. Christian Freise & Hyunho Lee & Christopher Chronowski & Doug Chan & Jessica Cziomer & Martin Rühl & Tarkan Dagdelen & Maik Lösekann & Ulrike Erben & Andre Catic & Werner Tegge & Detlef Schuppan & Raj, 2021. "Alpha-single chains of collagen type VI inhibit the fibrogenic effects of triple helical collagen VI in hepatic stellate cells," PLOS ONE, Public Library of Science, vol. 16(9), pages 1-18, September.
    5. Marie Bobowski-Gerard & Clémence Boulet & Francesco P. Zummo & Julie Dubois-Chevalier & Céline Gheeraert & Mohamed Bou Saleh & Jean-Marc Strub & Amaury Farce & Maheul Ploton & Loïc Guille & Jimmy Vand, 2022. "Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    6. Sonal Sinha & Satoka Aizawa & Yasuhiro Nakano & Alexander Rialdi & Hye Yeon Choi & Rajan Shrestha & Stephanie Q. Pan & Yibu Chen & Meng Li & Audrey Kapelanski-Lamoureux & Gregory Yochum & Linda Sher &, 2023. "Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Urban Lendahl & Lars Muhl & Christer Betsholtz, 2022. "Identification, discrimination and heterogeneity of fibroblasts," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. Ming Yang & Xiaoqiang Qi & Nan Li & Jussuf T. Kaifi & Shiyou Chen & Andrew A. Wheeler & Eric T. Kimchi & Aaron C. Ericsson & R. Scott Rector & Kevin F. Staveley-O’Carroll & Guangfu Li, 2023. "Western diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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