Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas, 78229-3900, USA.
Sci Rep. 2017 Oct 26;7(1):14157. doi: 10.1038/s41598-017-12672-1.
Connexin 43 (Cx43) is the most ubiquitous connexin in various cells, and presents as hemichannels (HCs) and gap junctions (GJs) on the cell membrane. We have recently shown that Cx43 abundance was strongly reduced in fibroblasts of human gingival wounds, and blocking Cx43 function in cultured human gingival fibroblasts (GFBLs) strongly regulated the expression of wound healing-related genes. However, it is not known whether these responses involved Cx43 HCs or GJs. Here we show that Cx43 assembled into distinct GJ and HC plaques in GFBLs both in vivo and in vitro. Specific blockage of Cx43 HC function by TAT-Gap19, a Cx43 mimetic peptide, significantly upregulated the expression of several MMPs, TGF-β signaling molecules, Tenascin-C, and VEGF-A, while pro-fibrotic molecules, including several extracellular matrix proteins and myofibroblast and cell contractility-related molecules, were significantly downregulated. These changes were linked with TAT-Gap19-induced suppression of ATP signaling and activation of the ERK1/2 signaling pathway. Collectively, our data suggest that reduced Cx43 HC function could promote fast and scarless gingival wound healing. Thus, selective suppression of Cx43 HCs may provide a novel target to modulate wound healing.
间隙连接蛋白 43（Cx43）在各种细胞中最为普遍，在细胞膜上表现为半通道（HCs）和缝隙连接（GJs）。我们最近发现，人牙龈创伤成纤维细胞中 Cx43 的丰度明显降低，在体外培养的人牙龈成纤维细胞（GFBLs）中阻断 Cx43 功能可强烈调节与伤口愈合相关的基因表达。然而，尚不清楚这些反应是否涉及 Cx43 HCs 或 GJs。在这里，我们表明 Cx43 在体内和体外的 GFBLs 中均组装成不同的 GJ 和 HC 斑。TAT-Gap19（一种 Cx43 模拟肽）特异性阻断 Cx43 HC 功能，可显著上调几种 MMPs、TGF-β 信号分子、Tenascin-C 和 VEGF-A 的表达，而促纤维化分子，包括几种细胞外基质蛋白和肌成纤维细胞和细胞收缩性相关分子，表达水平则显著下调。这些变化与 TAT-Gap19 诱导的 ATP 信号抑制和 ERK1/2 信号通路激活有关。总的来说，我们的数据表明，Cx43 HC 功能降低可能促进快速无瘢痕的牙龈伤口愈合。因此，选择性抑制 Cx43 HCs 可能为调节伤口愈合提供一个新的靶点。
