Connexin Communication Compartments and Wound Repair in Epithelial Tissue

Abstract

Epithelial tissues line the lumen of tracts and ducts connecting to the external environment. They are critical in forming an interface between the internal and external environment and, following assault from environmental factors and pathogens, they must rapidly repair to maintain cellular homeostasis. These tissue networks, that range from a single cell layer, such as in airway epithelium, to highly stratified and differentiated epithelial surfaces, such as the epidermis, are held together by a junctional nexus of proteins including adherens, tight and gap junctions, often forming unique and localised communication compartments activated for localised tissue repair. This review focuses on the dynamic changes that occur in connexins, the constituent proteins of the intercellular gap junction channel, during wound-healing processes and in localised inflammation, with an emphasis on the lung and skin. Current developments in targeting connexins as corrective therapies to improve wound closure and resolve localised inflammation are also discussed. Finally, we consider the emergence of the zebrafish as a concerted whole-animal model to study, visualise and track the events of wound repair and regeneration in real-time living model systems.

Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease

“…It is composed of a specialized stratified epithelium known as the epidermis. A key component of the epidermis are keratinocytes, which are located throughout the epithelium and can attach to the basal membrane, which serves as a boundary between the vascular dermis and avascular epidermis [46]. Epidermal keratinocytes are divided into the outer cornified layer, granular layer, spinous layer, and inner basal layer.…”

“…For example, the A-connexin carboxyl-terminal peptide (ACT-1) can accomplish that by targeting the carboxy tail of Cx43. This prevents any interaction with ZO-1 and results in increased gap junction plaque size [46,55] by competitively inhibiting the interaction between the PDZ binding domains on both proteins [52]. Notably, ACT-1 does not interfere with expression levels, suggesting the role it plays in wound healing is not likely to be facilitated by Cx43 expression.…”

Regeneration of airway epithelial cells to study rare cell states in cystic fibrosis

“…Several key signaling pathways regulate the continuous transition between proliferation and differentiation. First, AEC proliferation self-perpetuates until closure of the wound; wound closure triggers signals to stop proliferation via mechanisms that involve Notch and PPAR γ signaling [24] . The expression of Notch3 in some daughter cells coincides with the generation of early progenitors [ 25 , 26 ], while early differentiation is dependent on Notch1 and Notch2 signaling to give rise to SCs [27][28][29] .…”

Comparative Analysis of Cx31 and Cx43 in Differentiation-Competent Rodent Keratinocytes

“…Nowhere is this more evident than in the rodent epidermis where keratinocytes express mRNA for up to 9 connexins with Cx26, Cx30, Cx30.3, Cx31, Cx31.1, Cx37 and Cx43 readily expressed as detectable proteins [ 7 , 8 ]. These “keratinocyte connexins” are expressed at variable levels within the different strata of the epidermis to fulfil specific needs as these differentiating keratinocytes act to maintain epidermal homeostasis [ 8 , 9 , 10 , 11 ].…”