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A human liver cell atlas reveals heterogeneity and epithelial progenitors

Author

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  • Nadim Aizarani

    (Max-Planck-Institute of Immunobiology and Epigenetics
    University of Freiburg
    International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB))

  • Antonio Saviano

    (Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg
    Hôpitaux Universitaires)

  • Sagar

    (Max-Planck-Institute of Immunobiology and Epigenetics)

  • Laurent Mailly

    (Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Sarah Durand

    (Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Josip S. Herman

    (Max-Planck-Institute of Immunobiology and Epigenetics
    University of Freiburg
    International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB))

  • Patrick Pessaux

    (Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg
    Hôpitaux Universitaires)

  • Thomas F. Baumert

    (Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg
    Hôpitaux Universitaires)

  • Dominic Grün

    (Max-Planck-Institute of Immunobiology and Epigenetics
    University of Freiburg)

Abstract

The human liver is an essential multifunctional organ. The incidence of liver diseases is rising and there are limited treatment options. However, the cellular composition of the liver remains poorly understood. Here we performed single-cell RNA sequencing of about 10,000 cells from normal liver tissue from nine human donors to construct a human liver cell atlas. Our analysis identified previously unknown subtypes of endothelial cells, Kupffer cells, and hepatocytes, with transcriptome-wide zonation of some of these populations. We show that the EPCAM+ population is heterogeneous, comprising hepatocyte-biased and cholangiocyte populations as well as a TROP2int progenitor population with strong potential to form bipotent liver organoids. As a proof-of-principle, we used our atlas to unravel the phenotypic changes that occur in hepatocellular carcinoma cells and in human hepatocytes and liver endothelial cells engrafted into a mouse liver. Our human liver cell atlas provides a powerful resource to enable the discovery of previously unknown cell types in normal and diseased livers.

Suggested Citation

  • Nadim Aizarani & Antonio Saviano & Sagar & Laurent Mailly & Sarah Durand & Josip S. Herman & Patrick Pessaux & Thomas F. Baumert & Dominic Grün, 2019. "A human liver cell atlas reveals heterogeneity and epithelial progenitors," Nature, Nature, vol. 572(7768), pages 199-204, August.
    • Handle: RePEc:nat:nature:v:572:y:2019:i:7768:d:10.1038_s41586-019-1373-2
    DOI: 10.1038/s41586-019-1373-2
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    1. T. Hautz & S. Salcher & M. Fodor & G. Sturm & S. Ebner & A. Mair & M. Trebo & G. Untergasser & S. Sopper & B. Cardini & A. Martowicz & J. Hofmann & S. Daum & M. Kalb & T. Resch & F. Krendl & A. Weisse, 2023. "Immune cell dynamics deconvoluted by single-cell RNA sequencing in normothermic machine perfusion of the liver," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Jie Liao & Jingyang Qian & Yin Fang & Zhuo Chen & Xiang Zhuang & Ningyu Zhang & Xin Shao & Yining Hu & Penghui Yang & Junyun Cheng & Yang Hu & Lingqi Yu & Haihong Yang & Jinlu Zhang & Xiaoyan Lu & Li , 2022. "De novo analysis of bulk RNA-seq data at spatially resolved single-cell resolution," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Shanshan Guo & Yonghao Feng & Xiaopeng Zhu & Xinyi Zhang & Hui Wang & Ruwen Wang & Qiongyue Zhang & Yiming Li & Yan Ren & Xin Gao & Hua Bian & Tiemin Liu & Huanqing Gao & Xingxing Kong, 2023. "Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Delilah Hendriks & Benedetta Artegiani & Thanasis Margaritis & Iris Zoutendijk & Susana Chuva de Sousa Lopes & Hans Clevers, 2024. "Mapping of mitogen and metabolic sensitivity in organoids defines requirements for human hepatocyte growth," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Ting Dong & Guangan Hu & Zhongqi Fan & Huirui Wang & Yinghui Gao & Sisi Wang & Hao Xu & Michael B. Yaffe & Matthew G. Vander Heiden & Guoyue Lv & Jianzhu Chen, 2024. "Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    6. Joachim Jonghe & Tomasz S. Kaminski & David B. Morse & Marcin Tabaka & Anna L. Ellermann & Timo N. Kohler & Gianluca Amadei & Charlotte E. Handford & Gregory M. Findlay & Magdalena Zernicka-Goetz & Sa, 2023. "spinDrop: a droplet microfluidic platform to maximise single-cell sequencing information content," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    7. Franziska Hildebrandt & Alma Andersson & Sami Saarenpää & Ludvig Larsson & Noémi Van Hul & Sachie Kanatani & Jan Masek & Ewa Ellis & Antonio Barragan & Annelie Mollbrink & Emma R. Andersson & Joakim L, 2021. "Spatial Transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    8. Aleksandr Ianevski & Anil K. Giri & Tero Aittokallio, 2022. "Fully-automated and ultra-fast cell-type identification using specific marker combinations from single-cell transcriptomic data," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    9. Laura Rüland & Francesco Andreatta & Simone Massalini & Susana Chuva de Sousa Lopes & Hans Clevers & Delilah Hendriks & Benedetta Artegiani, 2023. "Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    10. Erica Carolina & Yoshiki Kuse & Ayumu Okumura & Kenji Aoshima & Tomomi Tadokoro & Shinya Matsumoto & Eriko Kanai & Takashi Okumura & Toshiharu Kasai & Souichiro Yamabe & Yuji Nishikawa & Kiyoshi Yamag, 2024. "Generation of human iPSC-derived 3D bile duct within liver organoid by incorporating human iPSC-derived blood vessel," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    11. James T. Topham & Erica S. Tsang & Joanna M. Karasinska & Andrew Metcalfe & Hassan Ali & Steve E. Kalloger & Veronika Csizmok & Laura M. Williamson & Emma Titmuss & Karina Nielsen & Gian Luca Negri & , 2022. "Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    12. Elisa I. Rivas & Jenniffer Linares & Melissa Zwick & Andrea Gómez-Llonin & Marc Guiu & Anna Labernadie & Jordi Badia-Ramentol & Anna Lladó & Lídia Bardia & Iván Pérez-Núñez & Carolina Martínez-Ciarpag, 2022. "Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    13. Inmaculada Ruz-Maldonado & John T. Gonzalez & Hanming Zhang & Jonathan Sun & Alicia Bort & Inamul Kabir & Richard G. Kibbey & Yajaira Suárez & Daniel M. Greif & Carlos Fernández-Hernando, 2024. "Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    14. Lei Xiong & Kang Tian & Yuzhe Li & Weixi Ning & Xin Gao & Qiangfeng Cliff Zhang, 2022. "Online single-cell data integration through projecting heterogeneous datasets into a common cell-embedding space," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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