Smaddening complexity: the role of Smad3 in epithelial-myofibroblast transition.
Epithelial-mesenchymal transition (EMT) has emerged as a major mechanism in the pathogenesis of organ fibrosis. The epithelium has been proposed to be a significant source of matrix-producing fibroblasts and of myofibroblasts (MFs), a motile and contractile cell type hallmarked by the expression of α-smooth muscle actin (SMA). Importantly, tissue accumulation of MFs shows strong correlation with the severity and progression of fibrotic diseases. The pleiotropic cytokine transforming growth factor-β(1) has been long known as the chief inducer of fibrosis, EMT and MF generation. Accordingly, receptor Smads (Smad2 and particularly Smad3), the direct targets of the activated transforming growth factor-β receptor have been implicated as critical mediators in fibrogenesis and EMT. However, evidence is accumulating that the role of Smad3 is complex and apparently controversial; in fact, Smad3 may differentially affect the various components of EMT, including the loss of epithelial markers (de-epithelialization), the production of extracellular matrix (fibrogenesis) and the expression of SMA (myogenic program). In this review, we revisit the role of Smad3 in epithelial-myofibroblast transition (EMyT). We first summarize the evidence supporting the thesis that Smad3 is a key mediator of EMT and MF generation; next, we present evidence supporting the antithesis that Smad3 is in fact a negative regulator of SMA expression and the activation of the myogenic program in the epithelium; finally, we propose a synthesis, which depicts Smad3 as a timekeeper and context-dependent modulator of EMyT. We suggest that EMyT is composed of an early, mesenchymal, Smad3-promoted phase and a late, myogenic, Smad3-inhibitable phase.
Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Department of Surgery, University of Toronto, Toronto, Ont., Canada.
András
A
Masszi
András
A
Kapus
D000818:Animals; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*
D051900:Smad3 Protein