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

Abstract

IntroductionCD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix.ObjectiveTo determine the role of CD248 in the development of liver fibrosis in the rodent and human setting.DesignCD248 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 (CCl4) treatment.ResultsExpression 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 CCl4 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.ConclusionsOur 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.

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

“…As illustrated in Figure 7, we have identified multiple fibrogenic targets that meet these criteria: the PDGF/PDGFRβ system (29) and its downstream mediator CD248 (endosialin) (30), which promote the differentiation of quiescent stellate cells into profibrotic myofibroblasts (Figure 7A); αvβ6 integrin, which is expressed in activated epithelial cells and is a marker of the progression of biliary and portal fibrosis as well as an activator of latent TGF-β (31) (Figure 7B); and the Nlrp3 inflammasome and its associate protein Asc3, which play a prominent role in liver inflammation associated with drug- or obesity-related liver fibrosis (32) (Figure 7C). Unique activation of these pathways by iNOS but not by CB 1 R may contribute to the differential antifibrotic efficacy of MRI-1867 and rimonabant.…”

Persistent stromal fibroblast activation is present in chronic tendinopathy

“…PDPN-expressing fibroblasts possess a pro-inflammatory phenotype in RA and malignancy [21, 22]. CD248-expressing fibroblasts have also been identified in hepatic and renal fibrosis, representing a reparative population [23]. …”

Hepatic stellate cells as key target in liver fibrosis

“…Small molecule tyrosine kinase inhibitors, including imatinib, sorafenib, nilotinib, and sunitinib, suppress proliferative and fibrogenic properties of activated HSCs in organotypic ex vivo culture of fibrotic human liver tissues [122–125]. CD248/endosialin is a PDGF downstream regulator of HSC proliferation during chronic liver injury [126]. A tyrosine phosphatase SHP-1 inhibits proliferation of activated HSCs via PDGF signaling [127].…”