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      Cellular and molecular mechanisms of repair in acute and chronic wound healing

      review-article
      1 , 2 , 2
      The British Journal of Dermatology
      John Wiley & Sons, Ltd

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          Abstract

          Summary

          A considerable understanding of the fundamental cellular and molecular mechanisms underpinning healthy acute wound healing has been gleaned from studying various animal models, and we are now unravelling the mechanisms that lead to chronic wounds and pathological healing including fibrosis. A small cut will normally heal in days through tight orchestration of cell migration and appropriate levels of inflammation, innervation and angiogenesis. Major surgeries may take several weeks to heal and leave behind a noticeable scar. At the extreme end, chronic wounds – defined as a barrier defect that has not healed in 3 months – have become a major therapeutic challenge throughout the Western world and will only increase as our populations advance in age, and with the increasing incidence of diabetes, obesity and vascular disorders. Here we describe the clinical problems and how, through better dialogue between basic researchers and clinicians, we may extend our current knowledge to enable the development of novel potential therapeutic treatments.

          What's already known about this topic?
          1. Much is known about the sequence of events contributing to normal healing.

          2. The two pathologies of wound healing are chronic wounds and scarring.

          What does this study add?
          1. We explain how the cell and molecular mechanisms of healing guide the therapeutic strategies.

          2. We introduce zebrafish and the fruit fly, Drosophila as novel wound healing models.

          3. We highlight unanswered questions and future directions for wound healing research.

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          Most cited references63

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          A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish

          Barrier structures (e.g. epithelia around tissues, plasma membranes around cells) are required for internal homeostasis and protection from pathogens. Wound detection and healing represent a dormant morphogenetic program that can be rapidly executed to restore barrier integrity and tissue homeostasis. In animals, initial steps include recruitment of leukocytes to the site of injury across distances of hundreds of micrometers within minutes of wounding. The spatial signals that direct this immediate tissue response are unknown. Due to their fast diffusion and versatile biological activities, reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are interesting candidates for wound-to-leukocyte signalling. We probed the role of H2O2 during the early events of wound responses in zebrafish larvae expressing a genetically encoded H2O2 sensor1. This reporter revealed a sustained rise in H2O2 concentration at the wound margin, starting ∼3 min after wounding and peaking at ∼20 min, which extended ∼100−200 μm into the tail fin epithelium as a decreasing concentration gradient. Using pharmacological and genetic inhibition, we show that this gradient is created by Dual oxidase (Duox), and that it is required for rapid recruitment of leukocytes to the wound. This is the first observation of a tissue-scale H2O2 pattern, and the first evidence that H2O2 signals to leukocytes in tissues, in addition to its known antiseptic role.
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            Distinct fibroblast lineages determine dermal architecture in skin development and repair

            Fibroblasts are the major mesenchymal cell type in connective tissue and deposit the collagen and elastic fibers of the extracellular matrix (ECM) 1 . Even within a single tissue fibroblasts exhibit remarkable functional diversity, but it is not known whether this reflects the existence of a differentiation hierarchy or is a response to different environmental factors. Here we show, using transplantation assays and lineage tracing, that the fibroblasts of skin connective tissue arise from two distinct lineages. One forms the upper dermis, including the dermal papilla that regulates hair growth and the arrector pili muscle (APM), which controls piloerection. The other forms the lower dermis, including the reticular fibroblasts that synthesise the bulk of the fibrillar ECM, and the pre-adipocytes and adipocytes of the hypodermis. The upper lineage is required for hair follicle formation. In wounded adult skin, the initial wave of dermal repair is mediated by the lower lineage and upper dermal fibroblasts are recruited only during re-epithelialisation. Epidermal beta-catenin activation stimulates expansion of the upper dermal lineage, rendering wounds permissive for hair follicle formation. Our findings explain why wounding is linked to formation of ECM-rich scar tissue that lacks hair follicles 2-4 . They also form a platform for discovering fibroblast lineages in other tissues and for examining fibroblast changes in ageing and disease.
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              Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding.

              The mammalian hair follicle is a complex 'mini-organ' thought to form only during development; loss of an adult follicle is considered permanent. However, the possibility that hair follicles develop de novo following wounding was raised in studies on rabbits, mice and even humans fifty years ago. Subsequently, these observations were generally discounted because definitive evidence for follicular neogenesis was not presented. Here we show that, after wounding, hair follicles form de novo in genetically normal adult mice. The regenerated hair follicles establish a stem cell population, express known molecular markers of follicle differentiation, produce a hair shaft and progress through all stages of the hair follicle cycle. Lineage analysis demonstrated that the nascent follicles arise from epithelial cells outside of the hair follicle stem cell niche, suggesting that epidermal cells in the wound assume a hair follicle stem cell phenotype. Inhibition of Wnt signalling after re-epithelialization completely abrogates this wounding-induced folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increases the number of regenerated hair follicles. These remarkable regenerative capabilities of the adult support the notion that wounding induces an embryonic phenotype in skin, and that this provides a window for manipulation of hair follicle neogenesis by Wnt proteins. These findings suggest treatments for wounds, hair loss and other degenerative skin disorders.
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                Author and article information

                Journal
                Br J Dermatol
                Br. J. Dermatol
                bjd
                The British Journal of Dermatology
                John Wiley & Sons, Ltd (Chichester, UK )
                0007-0963
                1365-2133
                August 2015
                14 July 2015
                : 173
                : 2
                : 370-378
                Affiliations
                [1 ]Schools of Biochemistry and Physiology & Pharmacology, University of Bristol Bristol, U.K
                [2 ]School of Medicine, University of Cardiff Cardiff, U.K
                Author notes
                Correspondence Paul Martin., E-mail: paul.martin@ 123456bristol.ac.uk

                Funding sources Wound healing studies in the Martin laboratory are supported by a programme grant from the Medical Research Council and a Wellcome Trust Investigator award.

                Conflicts of interest None declared.

                Article
                10.1111/bjd.13954
                4671308
                26175283
                14bb3232-2150-4187-b42f-2d2a3bf1e43c
                © 2015 The Authors British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 May 2015
                Categories
                Scholarly Reviews

                Dermatology
                Dermatology

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