Journal Article

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

Behnke, Kristina, Lehwald-Tywuschik, Nadja, Levkau, Bodo, Buschmann, Tobias, Ettich, Julia, Große-Segerath, Linda, Heinrich, Stefan, Kirschner, Philip, Lammert, Eckhard, Lehr, Stefan, Eberhard, Daniel, Korf-Klingebiel, Mortimer, Al-Hasani, Hadi, Follert, Paula, Hartwig, Sonja, Scheller, Jürgen, Wollert, Kai C., Knoefel, Wolfram Trudo

2024

Overview

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. After partial liver resection, the remaining liver blood vessels receive more blood flow and get mechanically stretched. Here the authors show that MYDGF is released from the stretched cells of these liver vessels, and that it is required and sufficient to promote liver regeneration and cell proliferation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/58 / 13 / 13/2 / 13/51 / 13/95 / 14/34 / 49/31 / 631/443 / 64/60 / 692/4020/4021/288/2032 / 82/1 / 82/80 / 96 / Animals / Blood flow / Blood vessels / Cell activation / Cell culture / Cell Proliferation / Endothelial cells / Endothelial Cells - metabolism / Growth factors / Hepatectomy / Hepatocytes / Hepatocytes - metabolism / Humanities and Social Sciences / Humans / Interleukins - metabolism / Kinases / Liver / Liver - metabolism / Liver Regeneration - physiology / MAP kinase / Mass spectrometry / Mass spectroscopy / Mice / Mitogen-Activated Protein Kinases - metabolism / multidisciplinary / Organoids / Science / Science (multidisciplinary) / Stat3 protein / Vasodilation