The current report by the Wells laboratory in HEPATOLOGY17 provides the strongest evidence against EMT in the liver as a source of myofibroblasts. This study uses lineage tracing generated by crossing the alpha-fetoprotein (AFP) cre mouse with the ROSA26YFP stop mouse to trace the fate of any cell ever expressing AFP (Fig. 1A). As expected, all the cholangiocytes and all the hepatocytes were genetically

labeled, because they are derived from AFP-expressing precursor cells. Furthermore, AFP+ progenitor cells were also irreversibly genetically marked. The critical result was that after inducing liver fibrosis by a variety of methods, none of the resulting myofibroblasts originated from the genetically marked epithelial (AFP+) cells. This important article corroborates and extends two previous studies in assessing the selleck inhibitor contribution of epithelial cells to myofibroblasts in liver fibrosis. The first article used the robust albumin cre mouse to mark all the hepatocytes.16 Pexidartinib price The second study used a recently developed inducible cytokeratin-19 cre mouse to

mark cholangiocytes.18 Both studies failed to detect any myofibroblasts in the fibrotic liver that originated from the epithelial cells. Thus, using three independent strains of cre mice as well as independent experimental methods (fluorescence-activated cell sorting, immunofluorescence to detect myofibroblast markers, and β-galactosidase enzymatic activity), these combined studies demonstrate that hepatic epithelial cells do not contribute to experimental liver fibrosis (Fig. 1B). So what are the caveats? The most obvious is that that these powerful techniques should be applied to assess EMT in additional experimental models in which there is severe injury to epithelial cells, such as in alcoholic liver disease. Furthermore, Epothilone B (EPO906, Patupilone) the short length of experimental liver fibrosis (3 weeks to 3 months) may not reflect the cellular pathophysiology

that occurs in chronic human liver disease, including the reactive ductile proliferation seen in patients. Therefore, the coexpression of epithelial and mesenchymal markers in cells from biopsies from patients with primary biliary cirrhosis or primary sclerosing cholangitis requires careful analysis and follow-up. Finally, studies consistently demonstrate that injured epithelial cells change their gene expression to produce fibrogenic agonists. Injured hepatocytes produce hedgehog ligands that activate stellate cells,19 and injured cholangiocytes produce the fibrogenic cytokine TGFβ.20 Thus, although there is no current evidence that myofibroblasts originate from hepatic epithelial cells, the original concept of type 2 EMT as injury-induced changes in epithelial cells continues to provide insight into liver fibrosis. “
“We read with interest the recent article by Sangro et al.