Molecular mechanisms of splenectomy-induced hepatocyte proliferation

Abstract

Functional and anatomical connection between the liver and the spleen is most clearly manifested in various pathological conditions of the liver (cirrhosis, hepatitis). The mechanisms of the interaction between the two organs are still poorly understood, as there have been practically no studies on the influence exerted by the spleen on the normal liver. Mature male Sprague-Dawley rats of 250-260 g body weight, 3 months old, were splenectomized. The highest numbers of Ki67+ hepatocytes in the liver of splenectomized rats were observed at 24 h after the surgery, simultaneously with the highest index of Ki67-positive hepatocytes. After surgical removal of the spleen, expression of certain genes in the liver tissues increased. A number of genes were upregulated in the liver at a single time point of 24 h, including Ccne1, Egf, Tnfa, Il6, Hgf, Met, Tgfb1r2 and Nos2. The expression of Ccnd1, Tgfb1, Tgfb1r1 and Il10 in the liver was upregulated over the course of 3 days after splenectomy. Monitoring of the liver macrophage populations in splenectomized animals revealed a statistically significant increase in the proportion of CD68-positive cells in the liver (as compared with sham-operated controls) detectable at 24 h and 48 h after the surgery. The difference in the liver content of CD68-positive cells between splenectomized and shamoperated animals evened out by day 3 after the surgery. No alterations in the liver content of CD163-positive cells were observed in the experiments. A decrease in the proportion of CD206-positive liver macrophages was observed at 48 h after splenectomy. The splenectomy-induced hepatocyte proliferation is described by us for the first time. Mechanistically, the effect is apparently induced by the removal of spleen as a major source of Tgfb1 (hepatocyte growth inhibitor) and subsequently supported by activation of proliferation factorencoding genes in the liver.

Comparative Analysis of the Transcriptome, Proteome, and miRNA Profile of Kupffer Cells and Monocytes

“…Thereafter, Laemmli Sample Buffer (Bio-Rad Laboratories, Inc., Hercules, CA, USA) was added with heating at 95 °C. The proteins were separated by 10%–12.5% sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to a membrane as described previously [ 57 ]. After blocking membranes were stained overnight with antibodies to Arg1, iNOs, CCR7, IL6, IL10, FXYD2, ALOX12, or GAPDH (anti-Arginase I: sc-18351, 1:200; anti-NOS2:sc-651, anti-GAPDH:sc-25778, Santa Cruz, USA, anti-CCR7:ab32527, anti-IL6:ab7737, anti-IL10:ab9969, Abcam, UK), anti-FXYD2:PA5-75640, anti-ALOX12:PA5-78760, ThermoScientific, Waltham, MA, USA), washed thrice, and stained with HRP-conjugated antibodies (Bio-Rad Laboratories, Inc., Hercules, CA, USA).…”

Effect of splenectomy based on inverse probability weighting of the propensity score on Wilson's disease with hypersplenism: A retrospective cohort study

“…In addition, splenectomy enhances the mitotic cycle of hepatocytes by reducing the release of anti-hepatocyte proliferation factor TGF-β1 from the spleen, thus promoting proliferation of hepatocytes (33). Therefore, improvement in liver function in patients with hypersplenism following splenectomy may be related to the reduction in the inflammatory response, promotion of hepatocyte proliferation, antifibrosis (34,35) and improvement in haemodynamics (36).…”

“…Studies have also shown that splenectomy in the early stage of liver fibrosis blocks rapid deployment of monocytes to the liver, thus reducing the inflammatory response and delaying the progression of early liver fibrosis in mice ( 31 , 32 ). In addition, splenectomy enhances the mitotic cycle of hepatocytes by reducing the release of anti-hepatocyte proliferation factor TGF-β1 from the spleen, thus promoting proliferation of hepatocytes ( 33 ). Therefore, improvement in liver function in patients with hypersplenism following splenectomy may be related to the reduction in the inflammatory response, promotion of hepatocyte proliferation, antifibrosis ( 34 , 35 ) and improvement in haemodynamics ( 36 ).…”

An Eye on Kupffer Cells: Development, Phenotype and the Macrophage Niche

“…The effect is accompanied by an increase in CD68+ macrophage counts in the lungs [ 131 ]. The coherence between monocyte/macrophage populations of the spleen and the liver is more comprehensible given the anatomical connection between the two organs via portal circulation [ 132 , 133 ]. At the same time, the spleen has been implicated as a monocyte supply for other organs as well.…”