The Role of Connexins in Wound Healing and Repair: Novel Therapeutic Approaches

Gap junctions are intercellular proteins responsible for mediating both electrical and biochemical coupling through the exchange of ions, second messengers and small metabolites. They consist of two connexons, with (one) connexon supplied by each cell. A connexon is a hexamer of connexins and currently more than 20 connexin isoforms have been described in the literature thus far. Connexins have a short half-life, and therefore gap junction remodeling constantly occurs with a high turnover rate. Post-translational modification, such as phosphorylation, can modify their channel activities. In this article, the roles of connexins in wound healing and repair are reviewed. Novel strategies for modulating the function or expression of connexins, such as the use of antisense technology, synthetic mimetic peptides and bioactive materials for the treatment of skin wounds, diabetic and pressure ulcers as well as cornea wounds, are considered.

• Publication year

  2016

• Venue

  Frontiers in Physiology

• Publication date

  2016-12-06

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3389/fphys.2016.00596PMID 27999549PMCID 5138227
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Gap Junction

  2020cited by this paper
• Mechanisms of Electrical Activation and Conduction in the Gastrointestinal System: Lessons from Cardiac Electrophysiology

  2016cited by this paper
• Anti-arrhythmic effects of hypercalcemia in hyperkalemic, Langendorff-perfused mouse hearts

  2016cited by this paper
• Ventricular anti-arrhythmic effects of heptanol in hypokalaemic, Langendorff-perfused mouse hearts

  2016cited by this paper
• Ventricular anti-arrhythmic effects of hypercalcaemia treatment in hyperkalaemic, Langendorff-perfused mouse hearts

  2016cited by this paper
• Connexins and pannexins in liver damage

  2016cited by this paper
• Both transmural dispersion of repolarization and of refractoriness are poor predictors of arrhythmogenicity: a role for iCEB (QT/QRS)?

  2016cited by this paper
• Bioglass promotes wound healing by affecting gap junction connexin 43 mediated endothelial cell behavior.

  2016cited by this paper
• Restitution analysis of alternans using dynamic pacing and its comparison with S1S2 restitution in heptanol-treated, hypokalaemic Langendorff-perfused mouse hearts

  2016cited by this paper
• Atrial Anti-Arrhythmic Effects of Heptanol in Langendorff-Perfused Mouse Hearts

  2016cited by this paper
• Gap junction inhibition by heptanol increases ventricular arrhythmogenicity by reducing conduction velocity without affecting repolarization properties or myocardial refractoriness in Langendorff-perfused mouse hearts

  2016cited by this paper
• Diabetes Increases Cryoinjury Size with Associated Effects on Cx43 Gap Junction Function and Phosphorylation in the Mouse Heart

  2015cited by this paper
• Manipulating Cx43 expression triggers gene reprogramming events in dermal fibroblasts from oculodentodigital dysplasia patients.

  2015cited by this paper
• Conduction abnormalities and ventricular arrhythmogenesis: The roles of sodium channels and gap junctions

  2015cited by this paper
• Applications of biomaterials in corneal wound healing

  2015cited by this paper
• Topical administration of a connexin43‐based peptide augments healing of chronic neuropathic diabetic foot ulcers: A multicenter, randomized trial

  2015influential reference
• Sodium channels in the Cx43 gap junction perinexus may constitute a cardiac ephapse: an experimental and modeling study

  2015cited by this paper
• The action of mimetic peptides on connexins protects fibroblasts from the negative effects of ischemia reperfusion

  2015cited by this paper
• Impact of the Controlled Release of a Connexin 43 Peptide on Corneal Wound Closure in an STZ Model of Type I Diabetes

  2014cited by this paper
• Specific Cx43 phosphorylation events regulate gap junction turnover in vivo

  2014cited by this paper
• Connexins, pannexins and innexins: Protein cousins with overlapping functions

  2014cited by this paper
• Mechanisms of cardiac conduction: a history of revisions.

  2014cited by this paper
• The Effect of a Connexin43-Based Peptide on the Healing of Chronic Venous Leg Ulcers: A Multicenter, Randomized Trial

  2014influential reference
• Corneal epithelial and neuronal interactions: role in wound healing.

  2014cited by this paper
• Gap junction and hemichannel‐independent actions of connexins on cell and tissue functions – An update

  2014cited by this paper
• Connexin expression patterns in diseased human corneas

  2014cited by this paper
• Cardiac to cancer: Connecting connexins to clinical opportunity

  2014influential reference
• Protective effects of carbenoxolone are associated with attenuation of oxidative stress in ischemic brain injury

  2013cited by this paper
• Gap junction remodeling in skin repair following wounding and disease.

  2013cited by this paper
• Connexin 43 is involved in the generation of human-induced pluripotent stem cells.

  2013cited by this paper
• Catecholamine stress alters neutrophil trafficking and impairs wound healing by β2 adrenergic receptor mediated upregulation of IL-6

  2013cited by this paper
• A synthetic connexin 43 mimetic peptide augments corneal wound healing.

  2013cited by this paper
• A Connexin43 Mimetic Peptide Promotes Regenerative Healing and Improves Mechanical Properties in Skin and Heart

  2013cited by this paper
• The use of connexin-based therapeutic approaches to target inflammatory diseases.

  2013cited by this paper
• A comparison of epithelial-to-mesenchymal transition and re-epithelialization.

  2012cited by this paper
• Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia.

  2012cited by this paper
• Mechanisms Involved in the Development and Healing of Diabetic Foot Ulceration

  2012cited by this paper
• Endothelial mesenchymal transformation mediated by IL-1β-induced FGF-2 in corneal endothelial cells.

  2012cited by this paper
• Barriers and more: functions of tight junction proteins in the skin

  2012cited by this paper
• Sertoli-cell-specific knockout of connexin 43 leads to multiple alterations in testicular gene expression in prepubertal mice

  2012cited by this paper
• Gap26, a connexin mimetic peptide, inhibits currents carried by connexin43 hemichannels and gap junction channels.

  2012cited by this paper
• Connexins in epidermal homeostasis and skin disease.

  2012cited by this paper
• Connexin43 phosphorylation in brain, cardiac, endothelial and epithelial tissues.

  2012cited by this paper
• Connexins in wound healing; perspectives in diabetic patients.

  2012cited by this paper
• Targeting Cx43 and N-Cadherin, Which Are Abnormally Upregulated in Venous Leg Ulcers, Influences Migration, Adhesion and Activation of Rho GTPases

  2012cited by this paper
• NorLeu3‐A(1–7) stimulation of diabetic foot ulcer healing: Results of a randomized, parallel‐group, double‐blind, placebo‐controlled phase 2 clinical trial

  2012cited by this paper
• Slug is upregulated during wound healing and regulates cellular phenotypes in corneal epithelial cells.

  2012cited by this paper
• Anatomy and physiology of the cornea

  2011cited by this paper
• Human dermal fibroblasts derived from oculodentodigital dysplasia patients suggest that patients may have wound‐healing defects

  2011cited by this paper
• TGF-β induces sustained upregulation of SNAI1 and SNAI2 through Smad and non-Smad pathways in a human corneal epithelial cell line.

  2011cited by this paper
• Inhibition of cytokine-induced connexin43 hemichannel activity in astrocytes is neuroprotective.

  2010cited by this paper
• Factors Affecting Wound Healing

  2010cited by this paper
• Connexin 43 mimetic peptide Gap27 reveals potential differences in the role of Cx43 in wound repair between diabetic and non-diabetic cells

  2010cited by this paper
• Slug inhibits proliferation of human prostate cancer cells via downregulation of cyclin D1 expression

  2010cited by this paper
• Connexin43 carboxyl-terminal peptides reduce scar progenitor and promote regenerative healing following skin wounding.

  2009cited by this paper
• Expression Pattern of Connexins in the Corneal and Limbal Epithelium of a Primate

  2009cited by this paper
• The Connexin43 Carboxyl-Terminal Peptide ACT1 Modulates the Biological Response to Silicone Implants

  2009cited by this paper
• [Effect of gap junction on the cardioprotection of ischemic postconditioning in rat heart].

  2009cited by this paper
• ATP release by cardiac myocytes in a simulated ischaemia model: inhibition by a connexin mimetic and enhancement by an antiarrhythmic peptide.

  2009cited by this paper
• Compression for venous leg ulcers.

  2009cited by this paper
• Hypoxia in high glucose followed by reoxygenation in normal glucose reduces the viability of cortical astrocytes through increased permeability of connexin 43 hemichannels

  2009cited by this paper
• Overexpression of connexin26 in the basal keratinocytes reduces sensitivity to tumor promoter TPA

  2009cited by this paper
• Targeting connexin 43 in diabetic wound healing: future perspectives.

  2009cited by this paper
• TGF-beta3 inhibits chondrogenesis of cultured chick leg bud mesenchymal cells via downregulation of connexin 43 and integrin beta4.

  2008cited by this paper
• Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing

  2008cited by this paper
• TGF‐β3 inhibits chondrogenesis of cultured chick leg bud mesenchymal cells via downregulation of connexin 43 and integrin β4

  2008cited by this paper
• Ischemia‐reperfusion injury in chronic pressure ulcer formation: A skin model in the rat

  2008cited by this paper
• A gene signature of nonhealing venous ulcers: potential diagnostic markers.

  2008cited by this paper
• Downregulation of connexin40 is associated with coronary endothelial cell dysfunction in streptozotocin-induced diabetic mice.

  2008cited by this paper
• Abnormal Connexin Expression Underlies Delayed Wound Healing in Diabetic Skin

  2007cited by this paper
• Differential regulation of key stages in early corneal wound healing by TGF-beta isoforms and their inhibitors.

  2006cited by this paper
• Alterations of connexin 43 in the diabetic rat heart.

  2006cited by this paper
• Ischemia Opens Neuronal Gap Junction Hemichannels

  2006cited by this paper
• Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response, enhanced keratinocyte proliferation and wound fibroblast migration

  2006cited by this paper
• The gap junction cellular internet: connexin hemichannels enter the signalling limelight.

  2006cited by this paper
• The Unstoppable Connexin43 Carboxyl‐Terminus

  2006cited by this paper
• Wound healing and its impairment in the diabetic foot.

  2005cited by this paper
• Bone Marrow Connexin-43 Expression Is Critical for Hematopoietic Regeneration After Chemotherapy

  2005cited by this paper
• Connexin 43 Interacts with Zona Occludens-1 and -2 Proteins in a Cell Cycle Stage-specific Manner*

  2005cited by this paper
• How the Cornea Heals: Cornea-specific Repair Mechanisms Affecting Surgical Outcomes

  2005cited by this paper
• Protein kinase C spatially and temporally regulates gap junctional communication during human wound repair via phosphorylation of connexin43 on serine368

  2004cited by this paper
• Connexins are mechanosensitive.

  2004cited by this paper
• Selective permeability of gap junction channels.

  2004cited by this paper
• Gap junctions and the connexin protein family.

  2004cited by this paper
• High Glucose Down-regulates Intercellular Communication in Retinal Endothelial Cells by Enhancing Degradation of Connexin 43 by a Proteasome-dependent Mechanism*

  2004cited by this paper
• Connexins 26, 30, and 43: differences among spontaneous, chronic, and accelerated human wound healing.

  2004influential reference
• TGF-β Signal Transduction in Corneal Wound Healing as a Therapeutic Target

  2004cited by this paper
• Characterization of Putative Stem Cell Phenotype in Human Limbal Epithelia

  2004cited by this paper
• Gap junction channel gating.

  2004cited by this paper
• Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy.

  2004cited by this paper
• Altered connexin expression and wound healing in the epidermis of connexin-deficient mice

  2003cited by this paper
• Dynamic changes in connexin expression correlate with key events in the wound healing process

  2003cited by this paper
• Molecular mechanisms controlling the fibrotic repair phenotype in cornea: implications for surgical outcomes.

  2003cited by this paper
• Targeting connexin43 expression accelerates the rate of wound repair.

  2003cited by this paper
• Connexin43 phosphorylation at S368 is acute during S and G2/M and in response to protein kinase C activation

  2003cited by this paper
• Accelerated wound closure in neutrophil‐depleted mice

  2003cited by this paper
• High glucose alters connexin 43 expression and gap junction intercellular communication activity in retinal pericytes.

  2003cited by this paper
• Epithelial–mesenchymal transitions in tumour progression

  2002cited by this paper
• Formation of the gap junction nexus: binding partners for connexins.

  2002cited by this paper
• Downregulation of connexin 43 expression by high glucose reduces gap junction activity in microvascular endothelial cells.

  2002cited by this paper

• Connexins are essential for the contribution of latent progenitors to self-repair after spinal cord injury

  2026cites this paper
• De Novo Gene Transcription of Connexin Mediates Cytoplasmic Fluid Exchange and Flocking Transitions in Physiological and Cancerous Epithelial Systems

  2025cites this paper
• Retinal calcium waves coordinate uniform tissue patterning of the Drosophila eye.

  2025cites this paper
• Retinal Calcium Waves Coordinate Uniform Tissue Patterning of the Drosophila Eye

  2025cites this paper
• Antioxidant-Rich Clitoria ternatea Flower Extract Promotes Proliferation and Migration of Human Corneal Epithelial Cells

  2025cites this paper
• Chemo-/radiotherapy-induced cardiomyopathy: roles of mitochondria and endoplasmic reticulum

  2025cites this paper
• Palmoplantar epidermal differentiation disorders: a new classification towards pathogenesis-based therapy.

  2025cites this paper
• Impact of diabetes on cellular connections: Pathological insights and emerging therapeutic targets.

  2025cites this paper
• Connexin-43 in Cancer: Above and Beyond Gap Junctions!

  2024cites this paper
• Trichohyalin gene expression is negatively correlated with the severity of dermatitis in a canine atopic dermatitis model

  2024cites this paper
• Connexins in epidermal health and diseases: insights into their mutations, implications, and therapeutic solutions

  2024cites this paper
• PKCμ promotes keratinocyte cell migration through Cx43 phosphorylation-mediated suppression of intercellular communication

  2024cites this paper
• Phenotypic and functional characterization of aqueous humor derived extracellular vesicles.

  2023cites this paper
• A Review of Gap Junction Protein and its Potential Role in Nervous System-Related Disease.

  2023cites this paper
• Nanoscale borosilicate bioactive glass for regenerative therapy of full-thickness skin defects in rabbit animal model

  2023cites this paper
• Robo4 inhibits gamma radiation-induced permeability of a murine microvascular endothelial cell by regulating the junctions

  2023cites this paper
• Is CEES a good analog of sulfur mustard? Macroscopic aspect, histology, and molecular biology comparisons between sulfur mustard and CEES-induced skin lesions.

  2022cites this paper
• The Expression of Connexin 37, 40, 43, 45 and Pannexin 1 in the Early Human Retina and Choroid Development and Tumorigenesis

  2022cites this paper
• Human Amniotic Mesenchymal Stem Cells and Fibroblasts Accelerate Wound Repair of Cystic Fibrosis Epithelium

  2022cites this paper
• Silibinin Promotes Bone Regeneration Through HIF-1α/VEGF and Notch Signaling Pathway in Ovariectomized Rats

  2021cites this paper
• Connexins and the Epithelial Tissue Barrier: A Focus on Connexin 26

  2021cites this paper
• Connexin43 gap junction drives fascia mobilization and repair of deep skin wounds.

  2021cites this paper
• The Complex and Critical Role of Glycine 12 (G12) in Beta-Connexins of Human Skin

  2021cites this paper
• Calcium signaling in the photodamaged skin

  2021cites this paper
• Molecular characteristics and spatial distribution of adult human corneal cell subtypes

  2021cites this paper
• Furnishing Wound Repair by the Subcutaneous Fascia

  2021cites this paper
• Calcium Signaling in the Photodamaged Skin: In Vivo Experiments and Mathematical Modeling

  2021cites this paper
• Connexin Signaling Is Involved in the Reactivation of a Latent Stem Cell Niche after Spinal Cord Injury

  2020cites this paper
• Functional properties of progenitor-like cells in the spinal cord

  2020cites this paper
• Scars or Regeneration?—Dermal Fibroblasts as Drivers of Diverse Skin Wound Responses

  2020cites this paper
• Connexins in melanoma: Potential role of Cx46 in its aggressiveness

  2020cites this paper
• Can bioactive glasses be useful to accelerate the healing of epithelial tissues?

  2019cites this paper
• The Role of Connexin-43 in the Inflammatory Process: A New Potential Therapy to Influence Keratitis

  2019cites this paper
• The Role of Connexins in Gastrointestinal Diseases.

  2019cites this paper
• Connexin43 Is Required for the Effective Activation of Spleen Cells and Immunoglobulin Production

  2019cites this paper
• Ex vivo culture of keratinocytes on papillary and reticular dermal layers remodels skin explants differently: towards improved wound care

  2019cites this paper
• Connexins: Synthesis, Post-Translational Modifications, and Trafficking in Health and Disease

  2018cites this paper
• Cartilage regeneration and ageing: Targeting cellular plasticity in osteoarthritis.

  2018cites this paper
• Review: Multimodal bioactive material approaches for wound healing

  2018cites this paper
• Therapeutic strategies targeting connexins

  2018cites this paper
• Regulation of connexin 43 expression in human gingival fibroblasts

  2018cites this paper
• Connexin-dependent intercellular stress signaling in tissue homeostasis and tumor development.

  2017cites this paper
• Connexins in the Central Nervous System: Physiological Traits and Neuroprotective Targets

  2017cites this paper
• Tachycardia-bradycardia syndrome: Electrophysiological mechanisms and future therapeutic approaches (Review)

  2017cites this paper
• The role of gap junctions in inflammatory and neoplastic disorders (Review)

  2017cites this paper
• Animal models of atherosclerosis

  2017cites this paper