The role of CD147 in liver injury: “The truth is in the details”
Authors: Susan V. McLennan, Fiona J. Warner, Nicholas A. Shackel
Journal: Journal of Hepatology (2012)

HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosisJournal of HepatologyVol. 57Issue 6PreviewActivated hepatic stellate cells (HSCs) located in the Disse's space play a crucial role in liver fibrosis. HAb18G/CD147, a tumor-related glycoprotein, is highly expressed in hepatocellular carcinoma cells and fibroblasts. Whether HAb18G/CD147 plays an important role in the hepatic fibrogenesis is unknown. Full-Text PDF Reply to: "The role of CD147 in liver injury: The truth is in the details"Journal of HepatologyVol. 58Issue 4PreviewWe greatly appreciate the letter by McLennan et al., which discusses our recently published article on the role of HAb18G/CD147 promoting liver fibrosis through activation of hepatic stellate cells (HSCs) [1]. Full-Text PDF Open Access We have read the manuscript by Zhang et al. with great interest [[1]Zhang D.W. Zhao Y.X. Wei D. Li Y.L. Zhang Y.Wu.J. Et at HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis.J hepatol. 2012; 57: 1283-1291Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. The results demonstrate an important role for CD147 in liver injury. However, we have published results, which are not referenced by Zhang et al. that appear to contradict some of their findings [[2]Shackel N.A. McGuinness P.H. Abbott C.A. Gorrell M.D. McCaughan G.W. Insights into the pathobiology of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression.Am J Pathol. 2002; 160: 641-654Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar]. Our immunohistochemistry staining for CD147 shows a pattern of expression consistent with hepatocyte and leukocyte specific expression, but with negligible expression by hepatic stellate cells (HSC) [[2]Shackel N.A. McGuinness P.H. Abbott C.A. Gorrell M.D. McCaughan G.W. Insights into the pathobiology of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression.Am J Pathol. 2002; 160: 641-654Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar]. We used a well-characterised commercial monoclonal antibody (MEM-M6/1) [2Shackel N.A. McGuinness P.H. Abbott C.A. Gorrell M.D. McCaughan G.W. Insights into the pathobiology of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression.Am J Pathol. 2002; 160: 641-654Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 3Koch C. Staffler G. Huttinger R. Hilgert I. Prager E. Cerny J. et al.T cell activation-associated epitopes of CD147 in regulation of the T cell response, and their definition by antibody affinity and antigen density.Int Immunol. 1999; 11: 777-786Crossref PubMed Scopus (128) Google Scholar], whilst HAb18G, the antibody used in the manuscript, is not commercially available [[1]Zhang D.W. Zhao Y.X. Wei D. Li Y.L. Zhang Y.Wu.J. Et at HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis.J hepatol. 2012; 57: 1283-1291Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. Confocal microscopy of CD147, using the antibody MEM-6/1, shows localisation with the CK-18 marker of hepatocytes, but not with α-smooth muscle actin (α-SMA) expressed by activated HSC (Fig. 1). The staining presented in Fig. 1A of the manuscript by Zhang et al. shows dense fibrous bands in cirrhosis that are strongly α-SMA positive, as expected [[1]Zhang D.W. Zhao Y.X. Wei D. Li Y.L. Zhang Y.Wu.J. Et at HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis.J hepatol. 2012; 57: 1283-1291Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. However, the adjacent panels in Fig. 1A of cirrhosis, stained with HAb18G for CD147, have a different pattern of expression [[1]Zhang D.W. Zhao Y.X. Wei D. Li Y.L. Zhang Y.Wu.J. Et at HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis.J hepatol. 2012; 57: 1283-1291Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. Therefore, we question the association of CD147 and α-SMA expression in the liver. A possible explanation is the heterogeneity in HSC populations as discussed by Zhang et al. [[1]Zhang D.W. Zhao Y.X. Wei D. Li Y.L. Zhang Y.Wu.J. Et at HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis.J hepatol. 2012; 57: 1283-1291Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. However, we have not observed such heterogeneity; there is no significant confocal microscopy co-localisation of MEM-6/1-stained CD147 expressing cells and α-SMA positive cells (Fig. 1). Further, we observe staining of hepatocytes [[2]Shackel N.A. McGuinness P.H. Abbott C.A. Gorrell M.D. McCaughan G.W. Insights into the pathobiology of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression.Am J Pathol. 2002; 160: 641-654Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar], which is not demonstrated in this manuscript (Fig. 1). We have confirmed these results by showing significant CD147 mRNA expression in primary isolated hepatocytes, which is comparable to whole liver tissue expression. Our results are in agreement with those published on the Human Protein Atlas [[4]Uhlen M. Oksvold P. Fagerberg L. Lundberg E. Jonasson K. Forsberg M. et al.Towards a knowledge-based Human Protein Atlas.Nat Biotechnol. 2010; 28: 1248-1250Crossref PubMed Scopus (1738) Google Scholar], and are consistent with data produced by other groups, showing CD147 expression in hepatocyte-derived cell lines [5Feng X. Xiu B. Xu L. Yang X. He J. Leong D. et al.Hepatitis C virus core protein promotes the migration and invasion of hepatocyte via activating transcription of extracellular matrix metalloproteinase inducer.Virus Res. 2011; 158: 146-153Crossref PubMed Scopus (13) Google Scholar, 6Wu J. Ru N.Y. Zhang Y. Li Y. Wei D. Ren Z. et al.HAb18G/CD147 promotes epithelial-mesenchymal transition through TGF-beta signaling and is transcriptionally regulated by Slug.Oncogene. 2011; 30: 4410-4427Crossref PubMed Scopus (138) Google Scholar]. A plausible explanation is, given that there are four major CD147 isoforms combined with varying glycosylation modifications of this widely expressed protein, that the different forms of CD147 are selectively targeted by different antibodies. Therefore, we believe the pattern of CD147 expression presented in the manuscript should be interpreted as being specific for the antibody used, and not generalised for all CD147 expression. It would be useful to have both high and low power views of the direct immunofluorescent staining of α-SMA and CD147 co-localisation. Additionally, Zhang et al. show in panel 3D that in the absence of CD147 overexpression, the HSC line LX-2 does not express α-SMA [[1]Zhang D.W. Zhao Y.X. Wei D. Li Y.L. Zhang Y.Wu.J. Et at HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis.J hepatol. 2012; 57: 1283-1291Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. However, in the original manuscript, in which LX-2 where isolated [[7]Xu L. Hui A.Y. Albanis E. Arthur M.J. O'Byrne S.M. Blaner W.S. et al.Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis.Gut. 2005; 54: 142-151Crossref PubMed Scopus (753) Google Scholar], and subsequent articles, it has been shown that LX-2 cells have an activated phenotype and do express α-SMA [[8]Lee T.F. Mak K.M. Rackovsky O. Lin Y.L. Kwong A.J. Loke J.C. et al.Downregulation of hepatic stellate cell activation by retinol and palmitate mediated by adipose differentiation-related protein (ADRP).J Cell Physiol. 2010; 223: 648-657PubMed Google Scholar]. Further, Zhang and colleagues have demonstrated that activated LX-2 HSC in vivo lack significant CD147 protein expression, when assessed by Western blot analysis (Fig. 3D) [[1]Zhang D.W. Zhao Y.X. Wei D. Li Y.L. Zhang Y.Wu.J. Et at HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis.J hepatol. 2012; 57: 1283-1291Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. Importantly, LX-2 exhibit multipotent behaviour and characteristics of bone marrow-derived mesenchymal stem cells and may not be the best model of in vivo HSC activation [[9]Castilho-Fernandes A. de Almeida D.C. Fontes A.M. Melo F.U. Picanco-Castro V. Freitas M.C. et al.Human hepatic stellate cell line (LX-2) exhibits characteristics of bone marrow-derived mesenchymal stem cells.Exp Mol Pathol. 2011; 91: 664-672Crossref PubMed Scopus (45) Google Scholar]. We commend the authors for this important work but think the role of CD147 in liver fibrosis is considerably more complex than that presented by Zhang et al. [[1]Zhang D.W. Zhao Y.X. Wei D. Li Y.L. Zhang Y.Wu.J. Et at HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis.J hepatol. 2012; 57: 1283-1291Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.