Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes
Linda Große‐Segerath, Paula Follert, Kristina Behnke, Julia Ettich, Tobias Buschmann, Philip Kirschner, Sonja Hartwig, Stefan Lehr, Mortimer Korf‐Klingebiel, Daniel Eberhard, Nadja Lehwald, Hadi Al‐Hasani, Wolfram Trudo Knoefel, Stefan Heinrich, Bodo Levkau, Kai C. Wollert, Jürgen Scheller, Eckhard Lammert
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.