Background In plastic surgery, tissue expansion is widely used for repairing skin defects. However, low expansion efficiency and skin rupture caused by thin, expanded skin remain significant challenges in promoting skin regeneration during expansion. S100 calcium-binding protein A9 (S100A9) is essential in promoting wound healing; however, its effects on skin regeneration during tissue expansion remain unclear. The aim of the present study was to explore the role of S100A9 in skin regeneration, particularly collagen production to investigate its importance in skin regeneration during tissue expansion. Methods The expression and distribution of S100A9 and its receptors—toll-like receptor 4 (TLR-4) and receptor for advanced glycation end products were studied in expanded skin. These characteristics were investigated in skin samples of rats and patients. Moreover, the expression of S100A9 was investigated in stretched keratinocytes in vitro. The effects of S100A9 on the proliferation and migration of skin fibroblasts were also observed. TAK-242 was used to inhibit the binding of S100A9 to TLR-4; the levels of collagen I (COL I), transforming growth factor beta (TGF-β), TLR-4 and phospho-extracellular signal-related kinase 1/2 (p-ERK1/2) in fibroblasts were determined. Furthermore, fibroblasts were co-cultured with stretched S100A9-knockout keratinocytes by siRNA transfection and the levels of COL I, TGF-β, TLR-4 and p-ERK1/2 in fibroblasts were investigated. Additionally, the area of expanded skin, thickness of the dermis, and synthesis of COL I, TGF-β, TLR-4 and p-ERK1/2 were analysed to determine the effects of S100A9 on expanded skin. Results Increased expression of S100A9 and TLR-4 was associated with decreased extracellular matrix (ECM) in the expanded dermis. Furthermore, S100A9 facilitated the proliferation and migration of human skin fibroblasts as well as the expression of COL I and TGF-β in fibroblasts via the TLR-4/ERK1/2 pathway. We found that mechanical stretch-induced S100A9 expression and secretion of keratinocytes stimulated COL I, TGF-β, TLR-4 and p-ERK1/2 expression in skin fibroblasts. Recombined S100A9 protein aided expanded skin regeneration and rescued dermal thinning in rats in vivo as well as increasing ECM deposition during expansion. Conclusions These findings demonstrate that mechanical stretch promoted expanded skin regeneration by upregulating S100A9 expression. Our study laid the foundation for clinically improving tissue expansion using S100A9.

中文翻译：

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S100钙结合蛋白A9在组织扩张过程中通过Toll样受体4促进皮肤再生

背景技术在整形外科中，组织扩张广泛用于修复皮肤缺陷。然而，扩张效率低以及薄扩张皮肤引起的皮肤破裂仍然是扩张过程中促进皮肤再生的重大挑战。S100钙结合蛋白A9（S100A9）对于促进伤口愈合至关重要；然而，其在组织扩张过程中对皮肤再生的影响仍不清楚。本研究的目的是探讨 S100A9 在皮肤再生中的作用，特别是胶原蛋白生成，以研究其在组织扩张过程中皮肤再生中的重要性。方法研究S100A9及其受体Toll样受体4（TLR-4）和晚期糖基化终末产物受体在扩张皮肤中的表达和分布。在大鼠和患者的皮肤样本中研究了这些特征。此外，在体外拉伸的角质形成细胞中研究了S100A9的表达。还观察了S100A9对皮肤成纤维细胞增殖和迁移的影响。TAK-242用于抑制S100A9与TLR-4的结合；测定成纤维细胞中胶原蛋白 I (COL I)、转化生长因子 β (TGF-β)、TLR-4 和磷酸细胞外信号相关激酶 1/2 (p-ERK1/2) 的水平。此外，通过siRNA转染将成纤维细胞与拉伸的S100A9敲除角质形成细胞共培养，并研究成纤维细胞中COL I、TGF-β、TLR-4和p-ERK1/2的水平。此外，还分析了扩张皮肤的面积、真皮的厚度以及COL I、TGF-β、TLR-4和p-ERK1/2的合成，以确定S100A9对扩张皮肤的影响。结果 S100A9 和 TLR-4 表达增加与扩张真皮中细胞外基质 (ECM) 减少相关。此外，S100A9通过TLR-4/ERK1/2途径促进人皮肤成纤维细胞的增殖和迁移以及成纤维细胞中COL I和TGF-β的表达。我们发现机械拉伸诱导的 S100A9 表达和角质形成细胞的分泌刺激了皮肤成纤维细胞中 COL I、TGF-β、TLR-4 和 p-ERK1/2 的表达。重组 S100A9 蛋白有助于大鼠体内皮肤再生的扩大和真皮变薄，并在扩张过程中增加 ECM 沉积。结论 这些发现表明机械拉伸通过上调 S100A9 表达来促进扩大的皮肤再生。我们的研究为临床上使用S100A9改善组织扩张奠定了基础。