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Abstract
Chronic overuse of common pharmaceuticals, e.g. acetaminophen (paracetamol), often leads to the development of acute liver failure (ALF). This study aimed to elucidate the effect of cultured mesenchymal stem cells (MSCs) proteome on the onset of liver damage and regeneration dynamics in animals with ALF induced by acetaminophen, to test the liver protective efficacy of MSCs proteome depending on the oxygen tension in cell culture, and to blueprint protein components responsible for the effect. Protein compositions prepared from MSCs cultured in mild hypoxic (5% and 10% O2) and normal (21% O2) conditions were used to treat ALF induced in mice by injection of acetaminophen. To test the effect of reduced oxygen tension in cell culture on resulting MSCs proteome content we applied a combination of high performance liquid chromatography and mass-spectrometry (LC–MS/MS) for the identification of proteins in lysates of MSCs cultured at different O2 levels. The treatment of acetaminophen-administered animals with proteins released from cultured MSCs resulted in the inhibition of inflammatory reactions in damaged liver; the area of hepatocyte necrosis being reduced in the first 24 h. Compositions obtained from MSCs cultured at lower O2 level were shown to be more potent than a composition prepared from normoxic cells. A comparative characterization of protein pattern and identification of individual components done by a cytokine assay and proteomics analysis of protein compositions revealed that even moderate hypoxia produces discrete changes in the expression of various subsets of proteins responsible for intracellular respiration and cell signaling. The application of proteins prepared from MSCs grown in vitro at reduced oxygen tension significantly accelerates healing process in damaged liver tissue. The proteomics data obtained for different preparations offer new information about the potential candidates in the MSCs protein repertoire sensitive to oxygen tension in culture medium, which can be involved in the generalized mechanisms the cells use to respond to acute liver failure.
Highlights
Materials and methodsAcute liver failure (ALF) caused by the intake of common pharmaceutical drugs is a well-known clinical problem worldwide
If the person taking the drug in therapeutic doses belongs to the group of so called “oversensitive” patients, this person can develop symptoms of liver damage, which vary from mild, transient liver disease to severe organ dysfunction, ending with acute liver failure (ALF) [1]
After 4 h, one-half to two-thirds of the lobule is spanned by the field of damaged hepatocytes in the form of severe protein and fatty degeneration and necrosis of individual cells or groups of them (Fig. 1a)
Summary
Materials and methodsAcute liver failure (ALF) caused by the intake of common pharmaceutical drugs is a well-known clinical problem worldwide. As shown in several clinical studies, individual susceptibility to drugs depends from the presence and activity of genes participating in the metabolism of xenobiotics and from functional activity of other genes regulating protective (primarily immune) systems of the organism [2]. Another reason for the development of ALF is intentional or accidental overuse of the drug by “normal”, non-“oversensitive” individuals. The hepatotoxicity caused by the overuse of acetaminophen is the most common cause of ALF and accounts for about 50% of all clinical cases [4]
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