Abstract
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.
Highlights
We have previously shown that in vivo human gingival fibroblasts (GFBLs) assemble Connexin 43 (Cx43) into large plaques typical of GJs37, but it is unclear whether these cells possess Cx43 HCs in vivo
The findings in the present study showed that Cx43 assembles into distinct plaques in GFBLs in vivo and in vitro
Based on immunostaining of tissue sections and GFBL cultures using Cx43 antibodies that recognizes total Cx43 or only HC-associated Cx43, we further showed that some of these plaques were composed of Cx43 HCs while others localized to cell-cell contacts likely representing Cx43 gap junctions (GJs) plaques
Summary
Our recent findings have shown that in human oral mucosal gingival wounds, which heal faster and result in significantly less scarring than skin wounds[32,33,34,35,36], abundance of Cx43 plaques was strongly suppressed in wound fibroblasts, suggesting that reduced GJ and/or HC function may promote wound healing in gingiva[37]. Downregulation of Cx43 function may promote the GFBL phenotype conducive for efficient wound healing, but it is not clear whether these functions distinctly depended on Cx43 HCs or GJs. the aim of the present study was to characterize Cx43 HCs and GJs in human GFBLs, and determine their roles in regulating fibroblast gene expression relevant for wound healing. We hypothesized that Cx43 HCs and GJs distinctly regulate the expression of wound healing-associated genes in human GFBLs
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