Molecular mechanisms of splenectomy-induced hepatocyte proliferation

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 sham-operated 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 factor-encoding genes in the liver. Copyright: © 2020 Elchaninov et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Elchaninov A.V. 1, 2 , Fatkhudinov T.K. 2, 4 , Vishnyakova P.A. 1 , Nikitina M.P. 4 , Lokhonina A.V. 1 , Makarov A.V. 1, 3 , Arutyunyan I.V. 1 , Kananykhina E.Y. 4 , Poltavets A.S.1 , Butov K.R.3 , Baranov I.I.1 , Goldshtein D.V. 5 , Bolshakova G.B. 4 , Glinkina V.V. 3 , Sukhikh G.T.1
Public Library of Science
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  • 1 Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
  • 2 Histology Department, Peoples Friendship University of Russia, RUDN University, Moscow, Russian Federation
  • 3 Histology Department, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, Moscow, Russian Federation
  • 4 Laboratory of Growth and Development, Research Institute of Human Morphology, Moscow, Russian Federation
  • 5 Laboratory of Stem Cells Genetics, Research Center of Medical Genetics, Moscow, Russian Federation
Ключевые слова
CD163 antigen; CD68 antigen; Ki 67 antigen; mannose receptor; inducible nitric oxide synthase; interleukin 6; Nos2 protein, rat; transcriptome; transforming growth factor beta; animal experiment; animal tissue; Article; Ccnd1 gene; Ccne1 gene; cell proliferation; controlled study; epidermal growth factor gene; gene; gene expression; hepatocyte growth factor gene; interleukin 10 gene; interleukin 6 gene; liver cell; liver weight; macrophage; male; nonhuman; Nos2 gene; protein expression; proto oncogene c Met; rat; splenectomy; transforming growth factor beta 1 gene; transforming growth factor beta 1 receptor 1 gene; transforming growth factor beta 1 receptor 2 gene; tumor necrosis factor alpha gene; adverse event; animal; genetics; liver cell; metabolism; physiology; splenectomy; Sprague Dawley rat; Animals; Cell Proliferation; Hepatocytes; Interleukin-6; Macrophages; Male; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Splenectomy; Transcriptome; Transforming Growth Factor beta
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