title: The fate of the primary cilium during myofibroblast transition.
abstract: Myofibroblasts, the culprit of organ fibrosis, can originate from mesenchymal and epithelial precursors through fibroblast-myofibroblast and epithelial-myofibroblast transition (EMyT). Because certain ciliopathies are associated with fibrogenesis, we sought to explore the fate and potential role of the primary cilium during myofibroblast formation. Here we show that myofibroblast transition from either precursor results in the loss of the primary cilium. During EMyT, initial cilium growth is followed by complete deciliation. Both EMyT and cilium loss require two-hit conditions: disassembly/absence of intercellular contacts and transforming growth factor-β1 (TGFβ) exposure. Loss of E-cadherin-dependent junctions induces cilium elongation, whereas both stimuli are needed for deciliation. Accordingly, in a scratch-wounded epithelium, TGFβ provokes cilium loss exclusively along the wound edge. Increased contractility, a key myofibroblast feature, is necessary and sufficient for deciliation, since constitutively active RhoA, Rac1, or myosin triggers, and down-regulation of myosin or myocardin-related transcription factor prevents, this process. Sustained myosin phosphorylation and consequent deciliation are mediated by a Smad3-, Rac1-, and reactive oxygen species-dependent process. Transitioned myofibroblasts exhibit impaired responsiveness to platelet-derived growth factor-AA and sonic hedgehog, two cilium-associated stimuli. Although the cilium is lost during EMyT, its initial presence contributes to the transition. Thus myofibroblasts represent a unique cilium-less entity with profoundly reprogrammed cilium-related signaling.
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, and Department of Surgery, University of Toronto, Toronto, ON M5B 1T8, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Rozycki
authors.forename: Monika
authors.initials: M
authors.lastname: Lodyga
authors.forename: Jessica
authors.initials: J
authors.lastname: Lam
authors.forename: Maria Zena
authors.initials: MZ
authors.lastname: Miranda
authors.forename: Károly
authors.initials: K
authors.lastname: Fátyol
authors.forename: Pam
authors.initials: P
authors.lastname: Speight
authors.forename: András
authors.initials: A
authors.lastname: Kapus
mesh_terms: D054338:Cell Transdifferentiation; D004847:Epithelial Cells / Q000166:cytology / Q000648:ultrastructure; D005786:Gene Expression Regulation; D058628:Myofibroblasts / Q000166:cytology* / Q000648:ultrastructure; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D009218:Myosins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein