title: How do your contacts (or their absence) shape your fate?
abstract: Tissue accumulation of contractile myofibroblasts is a key feature of a multitude of fibrotic diseases. Myofibroblast generation either from epithelial or mesenchymal precursors involves the activation of a myogenic program, hallmarked by the expression of α-smooth muscle actin (SMA). Recent research suggests that this robust phenotypic reprogramming requires two critical inputs: the fibrogenic cytokine transforming growth factor-β1 (TGFβ) and an injury (or absence) of intercellular junctions. This two-hit paradigm of epithelial-myofibroblast transition (EMyT) postulates that the injured (contact-deprived) epithelium is locally and selectively sensitive (topically susceptible) to the transforming effect of TGFβ, while the intact areas are quite resistant to the phenotype-changing effect of this cytokine. Searching for molecular mechanisms underlying the synergy between contact injury and TGFβ, we found that an interplay among three multifunctional transcriptional (co)activators, the junction component β-catenin, the TGFβ receptor target Smad3, and the actin cytoskeleton-regulated myocardin-related transcription factor (MRTF) controls the magnitude and timing of SMA expression.(1) Moreover, this regulation is realized not only at the transcriptional level. Notably, these factors form a pretranscriptional circuit, in which they impact each other's activity and stability. Based on this recent paper we ponder about the mechanisms of cellular plasticity in the context of EMyT. We propose that topical susceptibility to TGFβ, triggered by cell contact-modulated pretranscriptional and transcriptional control is realized through the crosstalk of a few master regulators, whose coordinated action tailors SMA expression and contributes to the major decision of whether injury leads to healing or fibrosis.
authors.affiliation: Keenan Research Centre; Li Ka Shing Knowledge Institute; St. Michael's Hospital and Department of Surgery; University of Toronto; Toronto, ON Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Charbonney
authors.affiliation: Keenan Research Centre; Li Ka Shing Knowledge Institute; St. Michael's Hospital and Department of Surgery; University of Toronto; Toronto, ON Canada.
authors.forename: Pam
authors.initials: P
authors.lastname: Speight
authors.affiliation: Keenan Research Centre; Li Ka Shing Knowledge Institute; St. Michael's Hospital and Department of Surgery; University of Toronto; Toronto, ON Canada.
authors.forename: András
authors.initials: A
authors.lastname: Kapus
keywords: Smad3; TGFbeta signalng; epithelial plasticity; epithelial-mesenchymal transition; fibrosis; myelofibroblast; myocardin-related transcription facr; smooth muscle actin; β-catenin