Rozycki Matthew, Lodyga Monika, Lam Jessica, Miranda Maria Zena, Fátyol Károly, Speight Pam, Kapus András
Keenan Research Centre for Biomedical Science, St. Michael's Hospital, and Department of Surgery, University of Toronto, Toronto, ON M5B 1T8, Canada.
Mol Biol Cell. 2014 Mar;25(5):643-57. doi: 10.1091/mbc.E13-07-0429. Epub 2014 Jan 8.
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.
肌成纤维细胞是器官纤维化的元凶，可通过成纤维细胞 - 肌成纤维细胞转变和上皮 - 肌成纤维细胞转变（EMyT）分别源自间充质和上皮前体细胞。由于某些纤毛病与纤维化形成相关，我们试图探究初级纤毛在肌成纤维细胞形成过程中的命运和潜在作用。在此我们表明，无论是哪种前体细胞向肌成纤维细胞的转变都会导致初级纤毛的丧失。在EMyT过程中，纤毛最初生长，随后完全去纤毛化。EMyT和纤毛丧失都需要双重条件：细胞间接触的解体/缺失以及转化生长因子 -β1（TGFβ）暴露。E - 钙黏蛋白依赖性连接的丧失会诱导纤毛伸长，而两种刺激对于去纤毛化都是必需的。因此，在划痕损伤的上皮中，TGFβ仅沿伤口边缘引发纤毛丧失。收缩力增加是肌成纤维细胞的一个关键特征，对于去纤毛化是必要且充分的，因为组成型活性RhoA、Rac1或肌球蛋白会触发这一过程，而肌球蛋白或心肌素相关转录因子的下调则可阻止这一过程。持续的肌球蛋白磷酸化及随之而来的去纤毛化是由一个依赖Smad3、Rac1和活性氧的过程介导的。转变后的肌成纤维细胞对血小板衍生生长因子 -AA和音猬因子这两种与纤毛相关的刺激的反应性受损。尽管在EMyT过程中纤毛会丧失，但其最初的存在有助于这种转变。因此，肌成纤维细胞代表了一种独特的无纤毛实体，其与纤毛相关的信号传导已被深刻重编程。
