Hyaluronan Controls the Deposition of Fibronectin and Collagen and Modulates TGF-β1 Induction of Lung Myofibroblasts.
Hyaluronan Controls the Deposition of Fibronectin and Collagen and Modulates TGF-β1 Induction of Lung Myofibroblasts.
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DOI：
10.1016/j.matbio.2014.12.001
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Wight TN
中科院分区：
文献类型：
--
作者：
Evanko SP;Potter-Perigo S;Petty LJ;Workman GA;Wight TN
透明质酸依赖性细胞周基质对TGF-β1驱动的肌成纤维细胞诱导和维持的作用尚不清楚。Hybryonan是一种细胞外基质（ECM）糖胺聚糖，在细胞粘附、增殖和迁移中很重要，并与肌成纤维细胞的形成和维持有关。透明质酸的周转减少与肌成纤维细胞的分化和肺纤维化的增强有关。纤连蛋白是一种形成原纤维的粘附糖蛋白，其在用TGF-β1诱导后也上调。虽然它们是已知的相互结合，透明质酸和纤连蛋白之间的相互作用，在肌成纤维细胞诱导和基质组装的细胞周围基质还不清楚。本研究探讨了透明质酸的作用及其与肌成纤维细胞形成过程中纤维基质成分的相互作用。在TGF-β1诱导成肌纤维细胞后，透明质酸和纤连蛋白增加并共定位于ECM中。用4-甲基伞形酮（4-MU）抑制TGF-β1诱导的肺肌成纤维细胞中透明质酸合成4天，进一步增强了肌成纤维细胞形态，导致ECM中纤连蛋白和I型胶原沉积增加，α-平滑肌肌动蛋白和透明质酸合成酶2（HAS 2）mRNA表达增加。更有效地破坏细胞周围基质的低聚糖或透明质酸酶处理具有类似的效果。CD 44和β1整合素共定位于细胞膜和沿着一些应力纤维。然而，CD 44和透明质酸被明确排除在局灶性粘连之外，主要与皮质肌动蛋白相关。透明质酸酶消化的即时效应的延时成像显示，透明质酸基质主要介导局灶性接触之间的膜和皮质肌动蛋白的附着，表明通过透明质酸和CD 44的表面粘附与通过β1整联蛋白和纤连蛋白的局灶性粘附不同。荧光素标记的透明质酸规则地沿着纤连蛋白纤维结合，并且与β1整合素共定位较多，与CD 44共定位较少。因此，透明质酸基质可以干扰纤维状ECM组分的组装，并且这种相互作用调节肌成纤维细胞形成的程度。这些数据还表明，通过透明质酸基质的粘附影响细胞骨架组织，并且可能是通过影响纤连蛋白和胶原蛋白的粘附和组织来调节肌成纤维细胞的粘附和滑动的离合器机制的一部分。
The contribution of hyaluronan-dependent pericellular matrix to TGF-β1-driven induction and maintenance of myofibroblasts is not understood. Hyaluronan is an extracellular matrix (ECM) glycosaminoglycan important in cell adhesion, proliferation and migration, and is implicated in myofibroblast formation and maintenance. Reduced turnover of hyaluronan has been linked to differentiation of myofibroblasts and potentiation of lung fibrosis. Fibronectin is a fibril forming adhesive glycoprotein that is also upregulated following induction with TGF-β1. Although they are known to bind each other, the interplay between hyaluronan and fibronectin in the pericellular matrix during myofibroblast induction and matrix assembly is not clear. This study addresses the role of hyaluronan and its interaction with fibrillar matrix components during myofibroblast formation. Hyaluronan and fibronectin were increased and co-localized in the ECM following myofibroblast induction by TGF-β1. Inhibition of hyaluronan synthesis in TGF-β1-induced lung myofibroblasts over a 4 day period with 4-methyl umbelliferone (4-MU) further enhanced myofibroblast morphology, caused increased deposition of fibronectin and type I collagen in the ECM, and increased expression of alpha-smooth muscle actin and hyaluronan synthase 2 (HAS2) mRNA. Hyaluronan oligosaccarides or hyaluronidase treatment, which more effectively disrupted the pericellular matrix, had similar effects. CD44 and β1 integrins co-localized in the cell membrane and along some stress fibers. However, CD44 and hyaluronan were specifically excluded from focal adhesions, and associated primarily with cortical actin. Time-lapse imaging of the immediate effects of hyaluronidase digestion showed that hyaluronan matrix primarily mediates attachment of membrane and cortical actin between focal contacts, suggesting that surface adhesion through hyaluronan and CD44 is distinct from focal adhesion through β1 integrins and fibronectin. Fluorescein-labeled hyaluronan bound regularly along fibronectin fibers and co-localized more with β1 integrin and less with CD44. Therefore, the hyaluronan matrix can interfere with the assembly of fibrillar ECM components, and this interplay regulates the degree of myofibroblast formation. These data also suggest that adhesion through hyaluronan matrix impacts cytoskeletal organization, and is potentially part of a clutch mechanism that regulates stick and slip of myofibroblasts by affecting the adhesion to and organization of fibronectin and collagen.
透明质酸盐受体与肌动蛋白丝有关。
影响因子：
7.8
作者：
Lacy, B E;Underhill, C B
通讯作者：
Underhill, C B