Reduction of fibroblast size/mechanical force down-regulates TGF-β type II receptor: implications for human skin aging.
Reduction of fibroblast size/mechanical force down-regulates TGF-β type II receptor: implications for human skin aging.
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DOI：
10.1111/acel.12410
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发表时间：
2016-02
期刊：
影响因子：
7.8
通讯作者：
Quan T
中科院分区：
文献类型：
--
作者：
Fisher GJ;Shao Y;He T;Qin Z;Perry D;Voorhees JJ;Quan T
人皮肤的结构完整性在很大程度上取决于真皮细胞外基质（ECM）的质量，其由真皮成纤维细胞产生、组织和维持。通常，成纤维细胞附着于ECM，从而实现拉伸的细长形态。老化皮肤中真皮成纤维细胞的一个突出特征是尺寸减小，伸长率降低，形态更圆、塌陷。在这里，我们表明，在机械不受限制的三维胶原晶格中，成纤维细胞的尺寸减小与原子力显微镜测量的机械力减小相一致。减小的尺寸/机械力特异性下调TGF-β II型受体（TβRII），从而损害TGF-β/Smad信号通路。TβRII mRNA和蛋白质均减少，导致TGF-β与成纤维细胞结合丧失90%。TβRII的下调与其关键下游效应子Smad 3的磷酸化、DNA结合和转录活性显著降低以及Smad 3调节的ECM必需组分I型胶原、纤连蛋白和结缔组织生长因子（CTGF/CCN 2）表达降低相关。TβRII的恢复显著增加了TGF-β诱导Smad 3磷酸化和刺激ECM组分的表达。TβRII和ECM组分的表达减少响应于成纤维细胞尺寸减小/机械力，通过恢复尺寸/机械力完全逆转。在老年人皮肤中，成纤维细胞大小的减少与TβRII表达的减少和ECM产生的减少有关。总之，这些数据揭示了一种新的机制，为真皮ECM的损失提供了分子基础，伴随着脆性的增加，这是人类皮肤老化的一个突出特征。
The structural integrity of human skin is largely dependent on the quality of the dermal extracellular matrix (ECM), which is produced, organized, and maintained by dermal fibroblasts. Normally, fibroblasts attach to the ECM and thereby achieve stretched, elongated morphology. A prominent characteristic of dermal fibroblasts in aged skin is reduced size, with decreased elongation and a more rounded, collapsed morphology. Here, we show that reduced size of fibroblasts in mechanically unrestrained three‐dimensional collagen lattices coincides with reduced mechanical force, measured by atomic force microscopy. Reduced size/mechanical force specifically down‐regulates TGF‐β type II receptor (TβRII) and thus impairs TGF‐β/Smad signaling pathway. Both TβRII mRNA and protein were decreased, resulting in 90% loss of TGF‐β binding to fibroblasts. Down‐regulation of TβRII was associated with significantly decreased phosphorylation, DNA‐binding, and transcriptional activity of its key downstream effector Smad3 and reduced expression of Smad3‐regulated essential ECM components type I collagen, fibronectin, and connective tissue growth factor (CTGF/CCN2). Restoration of TβRII significantly increased TGF‐β induction of Smad3 phosphorylation and stimulated expression of ECM components. Reduced expression of TβRII and ECM components in response to reduced fibroblast size/mechanical force was fully reversed by restoring size/mechanical force. Reduced fibroblast size was associated with reduced expression of TβRII and diminished ECM production, in aged human skin. Taken together, these data reveal a novel mechanism that provides a molecular basis for loss of dermal ECM, with concomitant increased fragility, which is a prominent feature of human skin aging.