SFB 974: Communication and System Relevance in Liver Injury and Regeneration
Biology
Final Report Abstract
A number of seminal findings and concepts were recognised and developed within the framework of SFB 974. Hepatic stellate cells (HSC) were for the first time identified as mesenchymal stem cells of the liver, which are involved in liver regeneration by releasing trophic factors and differentiating into epithelial cells. The activation state of the HSC is influenced, among other things, by Reelin, Laminine and embryonic Ras. Furthermore, the space of Disse was for the first time described as a stem cell niche for stellate cells, and Laminin-521 and mechanostress were identified as important elements of this niche. Increased blood flow through the liver leads to the release of angiocrine signals not only from HSC but also from sinusoidal endothelial cells, which induce the proliferation of hepatocytes after partial hepatectomy (PHx) in mice. The absence of the mechanical stimulus after successful proliferation initiates the completion of the regeneration and thus acts as a "hepatostat". The decrease in mechanical stimuli with age could explain the reduced regenerative capacity of the aging liver. β1-integrins act as mechanosensors and mediate the regulation of cell function through changes in cell volume. But they also serve as receptors for taurine-conjugated ursodeoxycholic acid, which is used to treat cholestatic liver diseases. CD169+ cells, which can also produce interleukin 6 (IL-6) are significantly involved in liver regeneration after PHx as well as different macrophage populations. IL-6 trans-signaling via the soluble IL-6 receptor (sIL-6R) induces the expression of the liver growth factor HGF by hepatic stellate cells. IL-6 trans-signaling, but not classical signaling, controls liver regeneration following PHx. The expression of the lymphotoxin-β receptor (LTβR) on hepatocytes, but not on Kupffer cells, is essential for liver regeneration. Functional LTβR/TNFRp55 double deficient mice show complete abrogation of liver regeneration and analysis of these mice revealed so far undescribed LTβR modulated genes important for liver regeneration. Desialyzed platelets and IL-6 mediate increased hepatic thrombopoietin synthesis via the Ashwell-Morell receptor/ IL-6R-JAK2-STAT3 signaling pathway in liver damage. TNF and IL-6 signaling is controlled by ADAM17 and the central cofactor iRhom2. TNF receptors play a central role in viral infections by protecting CD169+ cells, which enable an antiviral immune response through forced virus replication. Bile acids have also been identified as restriction factors for viral infections and can have anti-inflammatory effects. The bile salt receptor TGR5, of which structural models could be created, is important. In biliary epithelial cells, TGR5 is essential for bile salt-dependent cell proliferation, cell protection, and chloride and bicarbonate secretion. TGR5 downregulation aggravates cholestatic liver damage, while TGR5 overexpression is protective. Such overexpression could also be demonstrated in cholangiocarcinoma, which promotes tumor growth. For the molecular study of the two human ABC transporters BSEP (ABCB11) and MDR3 (ABCB4), in vitro systems could be established, e.g. to determine the molecular consequences of disease-relevant mutations in ABCB11. In addition, the transport mechanism of ABCB4 was elucidated. Hepatic encephalopathy (HE), an important extrahepatic disorder in liver diseases, has been identified as a clinical manifestation of a low-grade glial edema with oxidative stress and subsequent disturbance of oscillatory networks in the brain. At the molecular level, ammonia-induced protein modifications such as protein tyrosine nitration and protein O-GlcNAcylation, RNA oxidation, cerebral gene expression changes, TNFR signaling, changes in autophagy and mitophagy as well as metabolic reprogramming through depletion of citrate cycle intermediates play an important role. Liver-specific deletion of glutamine synthetase and knockout of the taurine transporter TauT lead to systemic hyperammonemia. The underlying molecular mechanisms have been identified.
Publications
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Kroll T, Prescher M, Smits SHJ, Schmitt, L
(See online at https://doi.org/10.1021/acs.chemrev.0c00659)
