Jessica Lam's research while affiliated with University of Toronto and other places

Myofibroblasts, the culprit of organ fibrosis, can originate from mesenchymal and epithelial precursors, through fibroblast-myofibroblast and epithelial-myofibroblast transition (EMyT). Since 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 an initial cilium-growth is followed by complete deciliation. Both EMyT and cilium loss require two-hit conditions, i.e. disassembly/absence of intercellular contacts and TGFβ exposure. Loss of E-cadherin-dependent junctions induces cilium elongation while 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, while down-regulation of myosin or myocardin-related transcription factor prevents this process. Sustained myosin phosphorylation and the consequent deciliation are mediated by a Smad3-, Rac1- and ROS-dependent process. Transitioned myofibroblasts exhibit impaired responsiveness to PDGF-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 ciliumless entity with profoundly reprogrammed cilium-related signaling.