Mesenchymal stromal cell therapy for liver fibrosis

Substantial uncertainty exists from pre-clinical liver fibrosis models as to whether mesenchymal stromal cells (MSCs) are anti-fibrotic, and yet clinically they have been proposed as a putative anti-fibrotic therapy for patients. This research was set out to examine whether MSC therapy can reduce liver fibrosis. An assessment of the depth and persistence of fibrosis in two murine liver fibrosis models (12 doses of intraperitoneal carbon tetrachloride, or 16 weeks of oral thioacetamide) allowed a statistically powered analysis of MSC intervention. Human umbilical cord MSCs were peripherally injected after liver fibrosis was established, or during fibrogenesis. Finally, the effect of MSC conditioned medium on the biology of human stellate-cell line, LX2 cells, was examined. MSC administration neither resolved established fibrosis, nor abrogated fibrogenesis in either model. Peripherally injected MSCs were sequestered in the lungs. However, MSC conditioned medium attenuated the expression of collagen type-1 mRNA and promoted apoptosis in LX2 cells. The discordance between the in vivo and in vitro findings requires further exploration. Nevertheless, this statistically powered robust examination of human umbilical cord MSCs suggests no discernible anti-fibrotic influence in vivo, and future testing would require a significant deviation in protocol to overcome a documented barrier from this research

Clinical effectiveness of cell therapies in patients with chronic liver disease and acute-on-chronic liver failure: a systematic review protocol

PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to address in a systematic review protocol*. (DOC 82 kb

The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure

Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure

CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism

INTRODUCTION: CD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix. OBJECTIVE: To determine the role of CD248 in the development of liver fibrosis in the rodent and human setting. DESIGN: CD248 expression was studied by immunostaining and quantitative PCR in both normal and diseased human and murine liver tissue and isolated hepatic stellate cells (HSCs). Hepatic fibrosis was induced in CD248(−/−) and wild-type controls with carbon tetrachloride (CCl(4)) treatment. RESULTS: Expression of CD248 was seen in normal liver of humans and mice but was significantly increased in liver injury using both immunostaining and gene expression assays. CD248 was co-expressed with a range of fibroblast/HSC markers including desmin, vimentin and α-smooth muscle actin (α-SMA) in murine and human liver sections. CD248 expression was restricted to isolated primary murine and human HSC. Collagen deposition and α-SMA expression, but not inflammation and neoangiogenesis, was reduced in CD248(−/−) mice compared with wild-type mice after CCl(4) treatment. Isolated HSC from wild-type and CD248(−/−) mice expressed platelet-derived growth factor receptor α (PDGFR-α) and PDGFR-β at similar levels. As expected, PDGF-BB stimulation induced proliferation of wild-type HSC, whereas CD248(−/−) HSC did not demonstrate a proliferative response to PDGF-BB. Abrogated PDGF signalling in CD248(−/−) HSC was confirmed by significantly reduced c-fos expression in CD248(−/−) HSC compared with wild-type HSC. CONCLUSIONS: Our data show that deletion of CD248 reduces susceptibility to liver fibrosis via an effect on PDGF signalling, making it an attractive clinical target for the treatment of liver injury