Bacterial hepatocyte growth factor receptor agonist stimulates hepatocyte proliferation and accelerates liver regeneration in a partial hepatectomy rat model

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

Kalinin E.V. 1, 2 , Chalenko Y.M.1, 3 , Sysolyatina E.V.1 , Midiber K.Y.4 , Gusarov A.M.1 , Kechko O.I.5 , Kulikova A.A. 5 , Mikhaleva L.M.4 , Mukhachev A.Y.1 , Stanishevskyi Y.M. 2 , Mitkevich V.A.5 , Sobyanin K.A.1 , Ermolaeva S.A.1, 3
Wiley-Liss Inc.
  • 1 Gamaleya Research Center of Epidemiology and Microbiology, Moscow, Russian Federation
  • 2 Peoples' Friendship University of Russia (RUDN University), Moscow, Russian Federation
  • 3 Federal Research Center for Virology and Microbiology (FRCVM), Russian Academy of Sciences, Moscow, Russian Federation
  • 4 Research Institute of Human Morphology, Moscow, Russian Federation
  • 5 Engelhardt Institute of Molecular Biology, Moscow, Russian Federation
Ключевые слова
bacterial toxin; hepatocyte growth factor; InlB; Listeria monocytogenes; liver regeneration
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