1. Bacterial hepatocyte growth factor receptor agonist stimulates hepatocyte proliferation and accelerates liver regeneration in a partial hepatectomy rat model.
- Author
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Kalinin EV, Chalenko YM, Sysolyatina EV, Midiber KY, Gusarov AM, Kechko OI, Kulikova AA, Mikhaleva LM, Mukhachev AY, Stanishevskyi YM, Mitkevich VA, Sobyanin KA, and Ermolaeva SA
- Subjects
- Animals, Bacterial Proteins genetics, Cell Proliferation drug effects, Hep G2 Cells, Hepatectomy, Humans, Listeria monocytogenes, Male, Proto-Oncogene Proteins c-met genetics, Rats, Wistar, Recombinant Proteins pharmacology, Rats, Bacterial Proteins pharmacology, Liver Regeneration drug effects, Proto-Oncogene Proteins c-met agonists
- Abstract
Hepatocyte growth factor (HGF) is central to liver regeneration. The Internalin B (InlB) protein is a virulence factor produced by the pathogenic bacterium Listeria monocytogenes. InlB is known to mimic HGF activity by interacting with the HGF receptor (HGFR) and activating HGFR-controlled signaling pathways. We expressed and purified the HGFR-binding InlB domain, InlB321/15, cloned from the fully virulent clinical L. monocytogenes strain. HGFR and Erk1/2 phosphorylation was determined using Western blotting. The capacity of InlB321/15 to bind HGFR was measured using microscale thermophoresis. Liver regeneration was studied in a model of 70% partial hepatectomy (70%PHx) in male Wistar rats. The nuclear grade parameters were quantified using manual (percentage of binuclear hepatocytes), automated (nuclear diameters), or combined (Ki67 proliferation index) scoring methods. Purified InlB321/15 stimulated HGFR and Erk1/2 phosphorylation and accelerated the proliferation of HepG2 cells. InlB321/15 bound HGFR with Kd = 7.4 ± 1.3 nM. InlB321/15 injected intravenously on the second, fourth, and sixth days after surgery recovered the liver mass and improved the nuclear grade parameters. Seven days post 70% PHx, the liver weight indexes were 2.9 and 2.0%, the hepatocyte proliferation indexes were 19.8 and 0.6%, and the percentages of binucleated hepatocytes were 6.7 and 4.0%, in the InlB321/15-treated and control animals, respectively. Obtained data demonstrated that InlB321/15 improved hepatocyte proliferation and stimulated liver regeneration in animals with 70% hepatectomy., (© 2020 Wiley Periodicals LLC.)
- Published
- 2021
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