Connexin 43 deficiency accelerates skin wound healing and extracellular matrix remodeling in mice

Abstract

Background Cellular channels composed of connexin 43 are known to act as key players in the life cycle of the skin and consequently to underlie skin repair. Objective This study was specifically set up to investigate the suite of molecular mechanisms driven by connexin 43-based channels on wound healing. Methods To this end, a battery of parameters, including re-epithelialization, neovascularization, collagen deposition and extracellular matrix remodeling, was monitored over time during experimentally induced skin repair in heterozygous connexin 43 knockout mice. Results It was found that connexin 43 deficiency accelerates re-epithelialization and wound closure, increases proliferation and activation of dermal fibroblasts, and enhances the expression of extracellular matrix remodeling mediators. Conclusion These data substantiate the notion that connexin 43 may represent an interesting therapeutic target in dermal wound healing.

Involvement of connexin43 in acetaminophen-induced liver injury

“…Cx43 +/- mice were kindly provided by the International Agency for Research on Cancer (France) [21] and were backcrossed with WT C57BL/6 mice, and genotype was controlled as previously described [22]. Heterozygous Cx43-deficient mice were used, as the corresponding homozygous null mutation is lethal [21].…”

Connexin 43: Key roles in the skin

“…By contrast, the level of Cx43 expression remains at a low level throughout the entire healing process in humans (29). Cx43 reduction has been shown to be associated with: i) Remodeling of the extracellular matrix (ECM) (38); ii) proliferation and migration of keratinocytes and fibroblasts (10,39,40); and iii) regulation of inflammatory responses through certain cytokines, chemokines or growth factors (38,40). Transient knockdown or artificial deficiency of Cx43 induces the proliferation and migration of keratinocytes and dermal fibroblasts, and enhances ECM production by upregulating collagen type I, collagen type III, matrix metalloproteinase-2 and transforming growth factor (TGF)-β1 (38).…”

“…Cx43 reduction has been shown to be associated with: i) Remodeling of the extracellular matrix (ECM) (38); ii) proliferation and migration of keratinocytes and fibroblasts (10,39,40); and iii) regulation of inflammatory responses through certain cytokines, chemokines or growth factors (38,40). Transient knockdown or artificial deficiency of Cx43 induces the proliferation and migration of keratinocytes and dermal fibroblasts, and enhances ECM production by upregulating collagen type I, collagen type III, matrix metalloproteinase-2 and transforming growth factor (TGF)-β1 (38). Additionally, Cx43 knockdown may decrease the expression levels of chemokine (C-C motif) ligand 2 and tumor necrosis factor (TNF)α, and elevate the expression levels of TGF-β1 and collagen α1, which affects the extravasations of neutrophils and macrophages involved in the wound healing process (40).…”

A Multicenter Randomized Controlled Trial Evaluating a Cx43-Mimetic Peptide in Cutaneous Scarring

“…A large body of evidence support the role of connexins—a family of transmembrane proteins characterized by their capacity to form channels that directly link the cytoplasm of adjacent cells (gap junctions) or permit cell-extracellular paracrine communication (hemichannels)—as a potential antiscarring therapy (Ghatnekar et al, 2009; Qiu et al, 2003; Rhett et al, 2008). Cx43 is expressed in both epidermal and dermal cutaneous layers and has key regulatory assignments in wound repair and the processes of re-epithelialization, neovascularization, collagen deposition, and extracellular matrix remodeling (Churko et al, 2012; Cogliati et al, 2015; Ghatnekar et al, 2009; Hunter et al, 2005; Marquez-Rosado et al, 2012; Rhett et al, 2011). Hemichannels comprised of Cx43 are critical determinants of inflammatory, edematous, and fibrotic processes occurring in response to wounding, mediating purinergic signaling, and the release of proinflammatory and cytotoxic molecules (Calder et al, 2015; Lorraine et al, 2015; O’Carroll et al, 2013; Rhett et al, 2014).…”