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Role of connexin 43 in regulating wound healing-related gene expression in human skin and gingival fibroblasts

University of British Columbia

Wound healing in human oral mucosal gingiva is faster and results in significantly reduced scar formation as compared to similar skin wounds. Fibroblasts are the most abundant group of connective tissue cells that play a key role in wound healing and scar formation. It is possible that differential healing outcomes in skin and gingiva may relate to the distinct phenotypic features of fibroblasts residing in these tissues. In fibroblasts, cells-to-cell communication occurs partly through connexin (Cx) hemichannels (HCs) and gap junctions (GJs). Findings from previous studies have shown that functional blockage of connexin 43 (Cx43), the most ubiquitous Cx in skin (SFBLs) and gingival fibroblasts (GFBLs), accelerates wound closure in skin and may alleviate scarring, but the mechanisms are poorly understood and may involve modulation of Cx43 function in fibroblasts. In the present dissertation, we show that (1) Cx43 was the most abundant Cx present in cultured human SFBLs and GFBLs. (2) Its abundance was potently downregulated at the early stage of human gingival wound healing. (3) Cx43 assembled into GJ and HC plaques in skin and gingival epithelium and connective tissue fibroblasts, although its distribution into GJs or HCs was markedly different in these two tissues. (4) Cx43 mainly assembled into HCs in GFBLs while in SFBLs only a few HCs were present in vivo and in vitro. (5) Using an in vivo-like 3D culture model and Cx43 mimetic peptides to block its function, we showed that the GJ, HC, and channel-independent functions of Cx43 distinctly upregulate anti-fibrotic and downregulate profibrotic wound healing-related genes in GFBLs and SFBLs. (6) In GFBLs this response was mainly mediated by activation of ERK1/2 pathway via Cx43 HC blockage. Thus, Cx43 assembly into GJs and HCs and its function are distinct in SFBLs and GFBLs, which may contribute to the different wound healing outcomes in these tissues. Furthermore, specific blockage of Cx43 HC functions may provide a novel target to promote wound healing and alleviate scar formation.

Text

2018-03-16

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/64847

Craniofacial Science

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/