Targeting Connexin43 Expression Accelerates the Rate of Wound Repair

Abstract

The repair of tissue damage is a key survival process in all organisms and involves the coordinated activation of several cell types. Cell-cell communication is clearly fundamental to this process, and a great deal is known about extracellular communication within the wound site via cytokines. Here we show that direct cell-cell communication through connexin 43 (Cx43) gap junction channels also plays a major role in the wound healing process. In two different wound healing models, incisional and excisional skin lesions, we show that a single topical application of Cx43 antisense gel brings about a transient downregulation of Cx43 protein levels, and this results in a dramatic increase in the rate of wound closure. Cx43 knockdown reduces inflammation, seen both macroscopically, as a reduction in swelling, redness, and wound gape, and microscopically, as a significant decrease in neutrophil numbers in the tissue around the wound. One long-term consequence of the improved rate of healing is a significant reduction in the extent of granulation tissue deposition and the subsequent formation of a smaller, less distorted, scar. This approach is likely to have widespread therapeutic applications in other injured tissues and opens up new avenues of research into improving the wound healing process.

Identification of immune genes in grass carp Ctenopharyngodon idella in response to infection of the parasitic copepod Sinergasilus major

“…Several enzymes involved in metabolism were characterized, including ornithine decarboxylase antizyme, delta-6-fatty acyl desaturase, hexose-6-phosphate dehydrogenase, glucose phosphate isomerase A, branched chain alpha-keto acid dehydrogenase, and uridine phosphorylase. In addition, annexin A1 which involved in a diversity of cellular processes and connexin 43 in cell communication (Qiu et al 2003) have also been identified in the present study, and the latter is reported to have a major role in the process of wound healing (Qiu et al 2003).…”

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

“…188 Several connexins appear to be expressed in the skin, including Cx43, found in the epidermis and dermis and the potential for targeting this connexin has been extensively researched. [189][190][191] Numerous antisense-based therapies targeting Cx43 are in development. 188 …”

Defective channels lead to an impaired skin barrier

“…Gap junctions are major channels that allow cells to communicate with one another by facilitating intercellular communication, including the transfer of Ca 2+ , a fundamental ion in keratinocyte differentiation, and small molecules of ,1 kDa -such as inositol triphosphate (IP 3 ) -between cells. In the skin, gap junctions appear to regulate a number of cellular processes, including wound healing, differentiation and barrier function (Goliger and Paul, 1995;Coutinho et al, 2003;Qiu et al, 2003;Djalilian et al, 2006;Mori et al, 2006;Man et al, 2007;Kandyba et al, 2008;Simpson et al, 2013), and their role in epidermal integrity is reviewed elsewhere (Martin et al, 2014).…”