Matsuzaki Shinsuke, Hiratsuka Toru, Taniguchi Manabu, Shingaki Kenta, Kubo Tateki, Kiya Koichiro, Fujiwara Toshihiro, Kanazawa Shigeyuki, Kanematsu Ryutaro, Maeda Tameyasu, Takamura Hironori, Yamada Kohe, Miyoshi Ko, Hosokawa Ko, Tohyama Masaya, Katayama Taiichi
Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan; Department of Child Development and Molecular Brain Science, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan.
Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan.
PLoS One. 2015 Apr 30;10(4):e0123578. doi: 10.1371/journal.pone.0123578. eCollection 2015.
Recently, accumulating reports have suggested the importance of endoplasmic reticulum (ER) stress signaling in the differentiation of several tissues and cells, including myoblasts and osteoblasts. Secretory cells are easily subjected to ER stress during maturation of their secreted proteins. Skin fibroblasts produce and release several proteins, such as collagens, matrix metalloproteinases (MMPs), the tissue inhibitors of metalloproteinases (TIMPs) and glycosaminoglycans (GAGs), and the production of these proteins is increased at wound sites. Differentiation of fibroblasts into myofibroblasts is one of the key factors for wound healing and that TGF-β can induce fibroblast differentiation into myofibroblasts, which express α-smooth muscle actin. Well-differentiated myofibroblasts show increased production of collagen and TGF-β, and bring about wound healing. In this study, we examined the effects of ER stress signaling on the differentiation of fibroblasts, which is required for wound healing, using constitutively ER stress-activated primary cultured fibroblasts. The cells expressed positive α-smooth muscle actin signals without TGF-β stimulation compared with control fibroblasts. Gel-contraction assays suggested that ER stress-treated primary fibroblasts caused stronger shrinkage of collagen gels than control cells. These results suggest that ER stress signaling could accelerate the differentiation of fibroblasts to myofibroblasts at injured sites. The present findings may provide important insights for developing therapies to improve wound healing.
最近，越来越多的报道表明内质网（ER）应激信号在包括成肌细胞和成骨细胞在内的多种组织和细胞分化中具有重要作用。分泌细胞在其分泌蛋白成熟过程中容易受到内质网应激。皮肤成纤维细胞产生并释放多种蛋白质，如胶原蛋白、基质金属蛋白酶（MMPs）、金属蛋白酶组织抑制剂（TIMPs）和糖胺聚糖（GAGs），并且这些蛋白质在伤口部位的产生会增加。成纤维细胞向肌成纤维细胞的分化是伤口愈合的关键因素之一，转化生长因子-β（TGF-β）可诱导成纤维细胞分化为表达α-平滑肌肌动蛋白的肌成纤维细胞。分化良好的肌成纤维细胞胶原蛋白和TGF-β的产生增加，并促进伤口愈合。在本研究中，我们使用持续激活内质网应激的原代培养成纤维细胞，研究内质网应激信号对伤口愈合所需的成纤维细胞分化的影响。与对照成纤维细胞相比，这些细胞在没有TGF-β刺激的情况下表达阳性α-平滑肌肌动蛋白信号。凝胶收缩试验表明，内质网应激处理的原代成纤维细胞比对照细胞导致胶原蛋白凝胶更强的收缩。这些结果表明，内质网应激信号可以加速受伤部位成纤维细胞向肌成纤维细胞的分化。本研究结果可能为开发改善伤口愈合的治疗方法提供重要见解。
