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

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.

Therapeutic strategies to improve liver regeneration after hepatectomy

“…37 In the PHx liver, administration of anakinra, an IL-1 receptor antagonist, upregulated proliferating cell nuclear antigen (PCNA) compared with the vehicle-giving group. 38 Kalinin et al 39 demonstrated that treatment with the protein internalin B generated from Listeria monocytogenes , which mimics HGF, activated extracellular signal-regulated kinase and upregulated expression of cyclin D1 and CDK 2, 4 in rats with PHx. Wnt/β-catenin signaling is also shown to contribute to liver mass recovery.…”

A magnetic levitation-based system to study the mechanisms of bacterial flocculation and autoaggregation

“…Отсу тствие внешней опорной поверхности при формировании неприкрепленных агрегатов является важным отличием, указывающим на ограничения существующих моделей биопленок in vitro [10]. Скорее такие автоагрегаты, сформированные одним видом бактерий и не прикрепленные к поверхности, напоминают флокулы, хорошо известные микробиологам, изучающим поведение бактерий в естественных водоемах.…”

“…Как и биопленки, неприкрепленные агрегаты обеспечивают повышенную устойчивость к противомикробным препаратам [5]. С другой стороны, такие особенности, как потребность в бактериальной подвижности, состав матрикса и механизмы регуляции, могут различаться между неприкрепленными агрегатами и классическими биопленками [10].…”

The role of gut microbiota in liver regeneration

“…C-Met-deficient mice showed a higher mortality rate after 70% PH ( 60 ), suggesting the function of HGF/Met in liver regeneration. Listeria monocytogenes, a pathogenic bacterium can be found in various kinds of food, can enhance the effect of HGF through producing bacterial HGF receptor agonist InlB321/15 and thus promote liver regeneration after 70% PH ( 61 ). Lactiplantibacillus plantarum AR113 administration showed decline of phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidyl serine (PS), and lysophosphatidyl choline (LysoPC) levels in the serum of the rats and increase HGF secretion in liver after 70% PH ( 62 ).…”