Interleukin-1 Receptor Antagonist Modulates the Early Phase of Liver Regeneration after Partial Hepatectomy in Mice

Cytokine administration is a potential therapy for acute liver failure by reducing inflammatory responses and favour hepatocyte regeneration. The aim of this study was to evaluate the role of interleukin-1 receptor antagonist (IL-1ra) during liver regeneration and to study the effect of a recombinant human IL-1ra on liver regeneration

Progress of malignant mesothelioma research in basic science: a review of the 14th international conference of the international mesothelioma interest group (iMig2018)

Here we summarize the most recent update of mesothelioma research in basic science presented at the 14$^{th}$ iMig2018 international conference. The symposium of basic science track mainly focused on the drivers of mesothelioma initiation and progression, molecular pathogenesis, and perspectives on potential therapeutic approaches. This review covers several promising fields including strategies efficiently inhibiting YAP/TAZ functions or their critical downstream targets, heparanase inhibitors, RAN depletion, and MIF/CD74 inhibitors that may be developed as novel therapeutic approaches. In addition, targeting mesothelioma stem cells by depleting M2-polarized macrophages in tumor microenvironment or blocking Tnfsf18 (GITRL)-GITR signalling might be translated into therapeutic modalities in mesothelioma treatment

Fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver

Multipotent mesenchymal stromal cells (MSC) are currently investigated clinically as cellular therapy for a variety of diseases. Differentiation of MSC toward endodermal lineages, including hepatocytes and their therapeutic effect on fibrosis has been described but remains controversial. Recent evidence attributed a fibrotic potential to MSC. As differentiation potential might be dependent of donor age, we studied MSC derived from adult and pediatric human bone marrow and their potential to differentiate into hepatocytes or myofibroblasts in vitro and in vivo. Following characterization, expanded adult and pediatric MSC were co-cultured with a human hepatoma cell line, Huh-7, in a hepatogenic differentiation medium containing Hepatocyte growth factor, Fibroblast growth factor 4 and oncostatin M. In vivo, MSC were transplanted into spleen or liver of NOD/SCID mice undergoing partial hepatectomy and retrorsine treatment. Expression of mesenchymal and hepatic markers was analyzed by RT-PCR, Western blot and immunohistochemistry. In vitro, adult and pediatric MSC expressed characteristic surface antigens of MSC. Expansion capacity of pediatric MSC was significantly higher when compared to adult MSC. In co-culture with Huh-7 cells in hepatogenic differentiation medium, albumin expression was more frequently detected in pediatric MSC (5/8 experiments) when compared to adult MSC (2/10 experiments). However, in such condition pediatric MSC expressed alpha smooth muscle more strongly than adult MSC. Stable engraftment in the liver was not achieved after intrasplenic injection of pediatric or adult MSC. After intrahepatic injection, MSC permanently remained in liver tissue, kept a mesenchymal morphology and expressed vimentin and alpha smooth muscle actin, but no hepatic markers. Further, MSC localization merges with collagen deposition in transplanted liver and no difference was observed using adult or pediatric MSC. In conclusion, when transplanted into an injured or regenerating liver, MSC differentiated into myofibroblasts with development of fibrous tissue, regardless of donor age. These results indicate that MSC in certain circumstances might be harmful due to their fibrogenic potential and this should be considered before potential use of MSC for cell therapy

Expression of genes involved in liver regeneration.

<p>We analysed the expression of various genes implicated in liver regeneration (Bcl-xl, C/EBPα, C/EBPβ, c-myc, IGFBP-1 and PPARα) by real-time polymerase chain reaction at various time points 0 h, 4 h, 24 h, 48 h, 72 h post-hepatectomy. (A–H) Our results demonstrate that IGFBP-1 and C/EBPβ expression was significantly increased at 4 h in WT mice compared to IL-1ra KO (fold increase 59.1 vs. 15.3 for IGFBP-1 and 7.5 vs. 2.48 for C/EBPβ, respectively). Bcl-xl and c-myc expression was higher in WT mice but did not reach statistical significance. Expression level of C/EBPα and PPARα was similar. The fold increase was calculated for various time points and time 0 (0h) in control animals was used for normalization. *  =  Statistical significance p<0.05. WT  =  wild type, KO = knock-out, C/EBPα  =  CAAT enhancer binding protein α, C/EBPβ  =  CAAT enhancer binding protein β, IGFBP-1 =  Insulin-like growth factor binding protein 1, PPARα  =  Peroxisome proliferator-activated receptor alpha.</p

Measurement of alanine aminotransferase.

<p>Alanine aminotransferase (ALT) was analyzed on peripheral blood of WT mice treated with anakinra (n = 3) compared to WT mice without treatment (n = 3). Our results showed that alanine aminotransferase increase at 4h after partial hepatectomy and returned to normal levels after 72h. The levels of alanine aminotransferase of WT mice without treatment was significantly higher at 24h after partial hepatectomy compared to mice treated with anakinra (5 or 50mg/kg). For treated mice, there was no difference for the protective effect of anakinra between 5 and 50mg/kg. *  =  Statistical significance p<0.05. WT  =  wild type.</p

Analysis of Cyclin D1 expression in IL-1ra KO mice and in WT at early time points after hepatectomy.

<p>Expression of cell cycle protein Cyclin D1 was analysed by western blot analysis on native liver tissue recovered at 24 h, 48 h, 72 h, 5 days and 7 days after 70% hepatectomy in WT and IL-1ra KO mice. A) Western blot of cyclin D1. The quantification of bands of Cyclin D1 and actin are performed by densitometry. B) Cyclin D1 is significantly higher in WT mice compared to IL-1ra KO mice at 24 h and 48 h after 70% hepatectomy. Cyclin D1 increased significantly at 24 h in WT mice, and in IL-1ra KO mice at 48 h after hepatectomy. The results are expressed as a ratio of Cyclin D1 expression by actin expression. The quantification of bands of Cyclin D1 and actin are performed by densitometry. *  =  Statistical significance p<0.05. D  =  day, WT  =  wild type, KO  =  knock-out .</p