Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
Lab Invest. 2019 Dec;99(12):1861-1873. doi: 10.1038/s41374-019-0302-1. Epub 2019 Aug 13.
Hypertrophic scars (HSs) are characterized by fibroblast hyperproliferation and excessive matrix deposition. During wound healing, transforming growth factor (TGF)-β1/Smad signaling acts as a key regulator. As a transcriptional corepressor of TGF-β1/Smads, SnoN is expressed at low levels in many fibrotic diseases due to TGF-β1/Smad-induced degradation. SnoN residue (1-366; SR) is resistant to TGF-β1-induced degradation. However, the expression and role of SR in HSs are unknown. Here, we inhibited TGF-β1/Smad signaling via overexpression of SR to block fibroblast transdifferentiation, proliferation, and collagen deposition during HS formation. Our results showed that SnoN was downregulated in HS fibroblasts (HSFs) owing to TGF-β1/Smad-induced degradation. Overexpression of SR in normal human dermal fibroblasts (NHDFs) and HSFs successfully blocked phosphorylation of Smad2 and Smad3, thereby inhibiting NHDF transdifferentiation and HSF proliferation and reducing type I collagen (ColI) and type III collagen (ColIII) production and secretion. In addition, we applied overexpressed full-length SnoN (SF) and SR to wound granulation tissue in a rabbit model of HSs. SR reduced wound scarring, improved collagen deposition and arrangement of scar tissue, and decreased mRNA and protein expression of ColI, ColIII, and α-smooth muscle actin (α-SMA) more effectively than SF in vivo. These results suggest that SR could be a promising therapy for the prevention of HS.
增生性瘢痕（HSs）的特征是成纤维细胞过度增殖和细胞外基质过度沉积。在伤口愈合过程中，转化生长因子（TGF）-β1/Smad 信号通路作为关键调节因子发挥作用。SnoN 作为 TGF-β1/Smads 的转录核心抑制子，在许多纤维化疾病中由于 TGF-β1/Smad 诱导的降解而表达水平较低。SnoN 残基（1-366；SR）对 TGF-β1 诱导的降解具有抗性。然而，SR 在 HSs 中的表达和作用尚不清楚。在这里，我们通过过表达 SR 抑制 TGF-β1/Smad 信号通路，阻断 HS 形成过程中成纤维细胞的转分化、增殖和胶原沉积。研究结果表明，由于 TGF-β1/Smad 诱导的降解，SnoN 在 HS 成纤维细胞（HSFs）中表达下调。在正常人类真皮成纤维细胞（NHDFs）和 HSFs 中过表达 SR 可成功阻断 Smad2 和 Smad3 的磷酸化，从而抑制 NHDF 的转分化和 HSF 的增殖，并减少 I 型胶原（ColI）和 III 型胶原（ColIII）的产生和分泌。此外，我们将过表达全长 SnoN（SF）和 SR 应用于兔 HS 模型的创面肉芽组织中。SR 减少了创面瘢痕形成，改善了瘢痕组织的胶原沉积和排列，并且在体内比 SF 更有效地降低了 ColI、ColIII 和 α-平滑肌肌动蛋白（α-SMA）的 mRNA 和蛋白表达。这些结果表明，SR 可能是预防 HS 的一种有前途的治疗方法。
