Enhancing structural support of the dermal microenvironment activates fibroblasts, endothelial cells, and keratinocytes in aged human skin in vivo.
Enhancing structural support of the dermal microenvironment activates fibroblasts, endothelial cells, and keratinocytes in aged human skin in vivo.
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DOI：
10.1038/jid.2012.364
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Fisher GJ
中科院分区：
文献类型：
--
作者：
Quan T;Wang F;Shao Y;Rittié L;Xia W;Orringer JS;Voorhees JJ;Fisher GJ
真皮细胞外基质（ECM）为皮肤提供强度和弹性。ECM主要由成纤维细胞产生的I型胶原原纤维组成。成纤维细胞与胶原纤维的结合产生机械力，其调节细胞形态和功能。随着年龄的增长，胶原蛋白碎片减少了成纤维细胞-ECM结合和机械力，导致成纤维细胞收缩和功能降低，包括胶原蛋白的产生。在这里，我们报告说，这些年龄相关的变化在很大程度上是通过增强ECM的结构支持逆转。将真皮填充物、交联透明质酸注射到70岁以上的人的皮肤中，刺激成纤维细胞产生I型胶原蛋白。这种刺激与机械力的局部增加相关，由成纤维细胞伸长/伸展指示，并由II型TGF-β受体和结缔组织生长因子的上调介导。有趣的是，ECM的增强的机械支持也刺激成纤维细胞增殖，扩张脉管系统，并增加表皮厚度。与我们在人类皮肤中的观察结果一致，将填充物注射到真皮等同物培养物中会导致成纤维细胞的伸长，以及I型胶原蛋白的合成，这取决于TGF-β信号传导途径。因此，老年人皮肤中的成纤维细胞保持其功能活化的能力，其通过增强ECM的结构支撑而恢复。
The dermal extracellular matrix (ECM) provides strength and resiliency to skin. The ECM consists mostly of type I collagen fibrils, which are produced by fibroblasts. Binding of fibroblasts to collagen fibrils generates mechanical forces, which regulate cellular morphology and function. With aging, collagen fragmentation reduces fibroblast-ECM binding and mechanical forces, resulting in fibroblast shrinkage and reduced function including collagen production. Here, we report that these age-related alterations are largely reversed by enhancing structural support of the ECM. Injection of dermal filler, cross-linked hyaluronic acid, into the skin of persons over seventy years-old stimulates fibroblasts to produce type I collagen. This stimulation is associated with localized increased of mechanical forces, indicated by fibroblast elongation/spreading, and mediated by up-regulation of type II TGF-β receptor and connective tissue growth factor. Interestingly, enhanced mechanical support of the ECM also stimulates fibroblast proliferation, expands vasculature, and increases epidermal thickness. Consistent with our observations in human skin, injection of filler into dermal equivalent cultures causes elongation of fibroblasts, coupled with type I collagen synthesis, which is dependent on the TGF-β signaling pathway. Thus, fibroblasts in aged human skin retain their capacity for functional activation, which is restored by enhancing structural support of the ECM.
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