Evidence for and against Epithelial to Mesenchymal

29 The outcome of liver injury is determined by the success of repair. Liver repair 30 involves replacement of damaged liver tissue with healthy liver epithelial cells 31 (including both hepatocytes and cholangiocytes), and reconstruction of normal 32 liver structure and function. Current dogma posits that replication of surviving 33 mature hepatocytes and cholangiocytes drives the regeneration of liver 34 epithelium after injury, while failure of liver repair commonly leads to fibrosis, a 35 scaring condition in which hepatic stellate cells, the main liver-resident 36 mesenchymal cells, play the major role. The current review discusses other 37 mechanisms that might be responsible for the regeneration of new liver epithelial 38 cells and outgrowth of matrix-producing mesenchymal cells during hepatic injury. 39 This theory proposes that during liver injury, some epithelial cells undergo 40 epithelial-to-mesenchymal transition (EMT), acquire myofibroblastic 41 phenotypes/features and contribute to fibrogenesis, while certain mesenchymal 42 cells (namely hepatic stellate cells and stellate cell-derived myofibroblasts) 43 undergo mesenchymal-to-epithelial transition (MET), revert to epithelial cells, and 44 ultimately differentiate into either hepatocytes or cholangiocytes. Although this 45 theory is highly controversial, it suggests that the balance between EMT and 46 MET modulates the outcome of liver injury. This review summarizes recent 47 advances that support or refute the concept that certain types of liver cells are 48 capable of phenotype transition (i.e. EMT and MET) during both culture 49 conditions and chronic liver injury. 50