6, 7 One recently proposed scheme divides EMT into three distinct categories: type 1 occurring in development, type 2 in fibrosis, and type 3 in cancer and metastasis.6, 8 Type 1 EMT yields mesenchymal cells whereas type 2 yields fibroblasts which produce collagen, although they may or may not later become myofibroblasts.8 This is an important point when considering fibrosis in the liver

and other organs, because there is an abundance of data implicating α-smooth muscle actin (α-SMA)-positive myofibroblasts in matrix deposition.9, 10 As discussed below, many studies on EMT in fibrosis have failed to rigorously define EMT or to reconcile evidence of EMT with previous observations Fludarabine datasheet about the central role of myofibroblasts in fibrosis. Additionally, high-level collagen expression is not synonymous with a mesenchymal or fibroblast phenotype, although it is unquestionably the characteristic most relevant to fibrosis. EMT in fibrosis, although poorly defined in the literature, should incorporate two key elements: that cells lose their

epithelial identity, and that in this new state they deposit relevant amounts of collagen. In the absence of any suggestion that nonfibrogenic transitioned cells have a significant LBH589 role in fibrosis, convincing studies of EMT need to address both points. The identification of EMT in vivo is at the heart of the controversy over its role in fibrosis. Demonstrating motility, loss of cell-cell adhesion, and basement membrane breakdown in tissue samples is difficult given current methods, and many investigators have turned to surrogate markers of the epithelial and mesenchymal states as a means 上海皓元医药股份有限公司 of defining

EMT. Many of the markers in common use, however, are problematic because of a lack of specificity (e.g., vimentin) or because it is technically challenging to assess potentially subtle differences in localization or expression (e.g., epithelial markers like E-cadherin). The expression of fibroblast-specific protein 1 (FSP1, also referred to as S100A4) in cells with epithelial markers has been widely used to define EMT in vivo. This protein is reported to be specific for fibroblasts and to play a causal role in EMT.2 Significant data are emerging, however, questioning its specificity. In the kidney, carefully performed work suggests that FSP1 is a marker not of fibroblasts but rather of leukocytes and other, nonfibroblastic cell types.9, 11 This raises questions about the validity of studies postulating EMT on the basis of FSP1 staining, which includes most studies of EMT in liver fibrosis. Against this backdrop, Taura and colleagues used definitive marker analyses to readdress the question of whether hepatocytes undergo EMT and deposit collagen in the injured liver.12 In their article in this issue of HEPATOLOGY, they first investigated convincing reports that EMT occurs in hepatocytes in vitro.