Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival

Linda Lorenz, Jennifer Axnick, Tobias Buschmann, Carina Henning, Sofia Urner, Shentong Fang, Harri Nurmi, Nicole Eichhorst, Richard Holtmeier, Kálmán Bódis, Jong-Hee Hwang, Karsten Müssig, Daniel Eberhard, Jörg Stypmann, Oliver Kuss, Michael Roden, Kari Alitalo, Dieter Häussinger and Eckhard Lammert ()
Additional contact information
Linda Lorenz: Heinrich-Heine University
Jennifer Axnick: Heinrich-Heine University
Tobias Buschmann: Heinrich-Heine University
Carina Henning: Heinrich-Heine University
Sofia Urner: Heinrich-Heine University
Shentong Fang: The Centre of Excellence in Translational Cancer Biology, Biomedicum Helsinki, University of Helsinki
Harri Nurmi: The Centre of Excellence in Translational Cancer Biology, Biomedicum Helsinki, University of Helsinki
Nicole Eichhorst: Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine University
Richard Holtmeier: Division of Cardiology, University Clinic Münster
Kálmán Bódis: German Center for Diabetes Research (DZD e.V.)
Jong-Hee Hwang: Leibniz Center for Diabetes Research at Heinrich-Heine University
Karsten Müssig: German Center for Diabetes Research (DZD e.V.)
Daniel Eberhard: Heinrich-Heine University
Jörg Stypmann: Division of Cardiology, University Clinic Münster
Oliver Kuss: German Center for Diabetes Research (DZD e.V.)
Michael Roden: German Center for Diabetes Research (DZD e.V.)
Kari Alitalo: The Centre of Excellence in Translational Cancer Biology, Biomedicum Helsinki, University of Helsinki
Dieter Häussinger: Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine University
Eckhard Lammert: Heinrich-Heine University

Nature, 2018, vol. 562, issue 7725, 128-132

Abstract: Abstract Angiocrine signals derived from endothelial cells are an important component of intercellular communication and have a key role in organ growth, regeneration and disease1–4. These signals have been identified and studied in multiple organs, including the liver, pancreas, lung, heart, bone, bone marrow, central nervous system, retina and some cancers1–4. Here we use the developing liver as a model organ to study angiocrine signals5,6, and show that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, we demonstrate that vessel perfusion activates β1 integrin and vascular endothelial growth factor receptor 3 (VEGFR3). Notably, both β1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrate that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. Our findings uncover a signalling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance.

Keywords: Angiocrine Signals; Liver Growth; Adult Mouse Liver; Contrast-enhanced Ultrasound Measurements; FUJIFILM VisualSonics (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0522-3

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