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Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes

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  • Linda Große-Segerath

    (Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology
    Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University
    German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München)

  • Paula Follert

    (Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology)

  • Kristina Behnke

    (Heinrich Heine University Düsseldorf)

  • Julia Ettich

    (Heinrich Heine University Düsseldorf)

  • Tobias Buschmann

    (Heinrich Heine University Düsseldorf)

  • Philip Kirschner

    (Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology)

  • Sonja Hartwig

    (German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München
    Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty)

  • Stefan Lehr

    (German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München
    Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty)

  • Mortimer Korf-Klingebiel

    (Hannover Medical School)

  • Daniel Eberhard

    (Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology)

  • Nadja Lehwald-Tywuschik

    (Heinrich Heine University Düsseldorf)

  • Hadi Al-Hasani

    (German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München
    Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty)

  • Wolfram Trudo Knoefel

    (Heinrich Heine University Düsseldorf)

  • Stefan Heinrich

    (University Hospital Center Mainz)

  • Bodo Levkau

    (Heinrich Heine University Düsseldorf)

  • Kai C. Wollert

    (Hannover Medical School)

  • Jürgen Scheller

    (Heinrich Heine University Düsseldorf)

  • Eckhard Lammert

    (Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology
    Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University
    German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München)

Abstract

Recently, we have shown that after partial hepatectomy (PHx), an increased hepatic blood flow initiates liver growth in mice by vasodilation and mechanically-triggered release of angiocrine signals. Here, we use mass spectrometry to identify a mechanically-induced angiocrine signal in human hepatic endothelial cells, that is, myeloid-derived growth factor (MYDGF). We show that it induces proliferation and promotes survival of primary human hepatocytes derived from different donors in two-dimensional cell culture, via activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MYDGF also enhances proliferation of human hepatocytes in three-dimensional organoids. In vivo, genetic deletion of MYDGF decreases hepatocyte proliferation in the regenerating mouse liver after PHx; conversely, adeno-associated viral delivery of MYDGF increases hepatocyte proliferation and MAPK signaling after PHx. We conclude that MYDGF represents a mechanically-induced angiocrine signal and that it triggers growth of, and provides protection to, primary mouse and human hepatocytes.

Suggested Citation

  • Linda Große-Segerath & Paula Follert & Kristina Behnke & Julia Ettich & Tobias Buschmann & Philip Kirschner & Sonja Hartwig & Stefan Lehr & Mortimer Korf-Klingebiel & Daniel Eberhard & Nadja Lehwald-T, 2024. "Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44760-y
    DOI: 10.1038/s41467-024-44760-y
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    1. Rebecca Ebenhoch & Abbas Akhdar & Marc R. Reboll & Mortimer Korf-Klingebiel & Priyanka Gupta & Julie Armstrong & Yining Huang & Lee Frego & Irina Rybina & John Miglietta & Anton Pekcec & Kai C. Woller, 2019. "Crystal structure and receptor-interacting residues of MYDGF — a protein mediating ischemic tissue repair," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
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