Cheng Fang, Shen Yue, Mohanasundaram Ponnuswamy, Lindström Michelle, Ivaska Johanna, Ny Tor, Eriksson John E
Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520, Turku, Finland; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20521, Turku, Finland;
Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden; Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada V6Z 1Y6; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada V6Z 1Y6;
Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):E4320-7. doi: 10.1073/pnas.1519197113. Epub 2016 Jul 8.
Vimentin has been shown to be involved in wound healing, but its functional contribution to this process is poorly understood. Here we describe a previously unrecognized function of vimentin in coordinating fibroblast proliferation and keratinocyte differentiation during wound healing. Loss of vimentin led to a severe deficiency in fibroblast growth, which in turn inhibited the activation of two major initiators of epithelial-mesenchymal transition (EMT), TGF-β1 signaling and the Zinc finger transcriptional repressor protein Slug, in vimentin-deficient (VIM(-/-)) wounds. Correspondingly, VIM(-/-) wounds exhibited loss of EMT-like keratinocyte activation, limited keratinization, and slow reepithelialization. Furthermore, the fibroblast deficiency abolished collagen accumulation in the VIM(-/-) wounds. Vimentin reconstitution in VIM(-/-) fibroblasts restored both their proliferation and TGF-β1 production. Similarly, restoring paracrine TGF-β-Slug-EMT signaling reactivated the transdifferentiation of keratinocytes, reviving their migratory properties, a critical feature for efficient healing. Our results demonstrate that vimentin orchestrates the healing by controlling fibroblast proliferation, TGF-β1-Slug signaling, collagen accumulation, and EMT processing, all of which in turn govern the required keratinocyte activation.
波形蛋白已被证明参与伤口愈合，但其在这一过程中的功能作用仍知之甚少。在此，我们描述了波形蛋白在伤口愈合过程中协调成纤维细胞增殖和角质形成细胞分化的一种前所未有的功能。波形蛋白的缺失导致成纤维细胞生长严重不足，进而抑制了波形蛋白缺陷（VIM(-/-)）伤口中上皮-间质转化（EMT）的两个主要启动因子TGF-β1信号通路和锌指转录抑制蛋白Slug的激活。相应地，VIM(-/-)伤口表现出类似EMT的角质形成细胞激活丧失、角质化受限和上皮再形成缓慢。此外，成纤维细胞缺陷消除了VIM(-/-)伤口中的胶原蛋白积累。在VIM(-/-)成纤维细胞中重建波形蛋白可恢复其增殖和TGF-β1产生。同样，恢复旁分泌TGF-β-Slug-EMT信号通路可重新激活角质形成细胞的转分化，恢复其迁移特性，这是高效愈合的关键特征。我们的结果表明，波形蛋白通过控制成纤维细胞增殖、TGF-β1-Slug信号通路、胶原蛋白积累和EMT过程来协调愈合，所有这些反过来又控制所需的角质形成细胞激活。
