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      Cutaneous wound healing: recruiting developmental pathways for regeneration

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          Abstract

          Following a skin injury, the damaged tissue is repaired through the coordinated biological actions that constitute the cutaneous healing response. In mammals, repaired skin is not identical to intact uninjured skin, however, and this disparity may be caused by differences in the mechanisms that regulate postnatal cutaneous wound repair compared to embryonic skin development. Improving our understanding of the molecular pathways that are involved in these processes is essential to generate new therapies for wound healing complications. Here we focus on the roles of several key developmental signaling pathways (Wnt/β-catenin, TGF-β, Hedgehog, Notch) in mammalian cutaneous wound repair, and compare this to their function in skin development. We discuss the varying responses to cutaneous injury across the taxa, ranging from complete regeneration to scar tissue formation. Finally, we outline how research into the role of developmental pathways during skin repair has contributed to current wound therapies, and holds potential for the development of more effective treatments.

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          Most cited references191

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          Wound healing--aiming for perfect skin regeneration.

          P. Martin (1997)
          The healing of an adult skin wound is a complex process requiring the collaborative efforts of many different tissues and cell lineages. The behavior of each of the contributing cell types during the phases of proliferation, migration, matrix synthesis, and contraction, as well as the growth factor and matrix signals present at a wound site, are now roughly understood. Details of how these signals control wound cell activities are beginning to emerge, and studies of healing in embryos have begun to show how the normal adult repair process might be readjusted to make it less like patching up and more like regeneration.
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            Convergence of Wnt, beta-catenin, and cadherin pathways.

            W Nelson (2004)
            The specification and proper arrangements of new cell types during tissue differentiation require the coordinated regulation of gene expression and precise interactions between neighboring cells. Of the many growth factors involved in these events, Wnts are particularly interesting regulators, because a key component of their signaling pathway, beta-catenin, also functions as a component of the cadherin complex, which controls cell-cell adhesion and influences cell migration. Here, we assemble evidence of possible interrelations between Wnt and other growth factor signaling, beta-catenin functions, and cadherin-mediated adhesion.
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              TGF-β signaling in fibrosis.

              Transforming growth factor β (TGF-β) is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic diseases and modulates fibroblast phenotype and function, inducing myofibroblast transdifferentiation while promoting matrix preservation. Studies in a wide range of experimental models have demonstrated the involvement of the canonical activin receptor-like kinase 5/Smad3 pathway in fibrosis. Smad-independent pathways may regulate Smad activation and, under certain conditions, may directly transduce fibrogenic signals. The profibrotic actions of TGF-β are mediated, at least in part, through induction of its downstream effector, connective tissue growth factor. In light of its essential role in the pathogenesis of fibrosis, TGF-β has emerged as an attractive therapeutic target. However, the pleiotropic and multifunctional effects of TGF-β and its role in tissue homeostasis, immunity and cell proliferation raise concerns regarding potential side effects that may be caused by TGF-β blockade. This minireview summarizes the role of TGF-β signaling pathways in the fibrotic response.
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                Author and article information

                Contributors
                kirsten.bielefeld@mail.utoronto.ca
                saeid.amininik@utoronto.ca
                +1416-8137210 , +1-416-8132617 , benjamin.alman@sickkids.ca
                Journal
                Cell Mol Life Sci
                Cell. Mol. Life Sci
                Cellular and Molecular Life Sciences
                SP Birkhäuser Verlag Basel (Basel )
                1420-682X
                1420-9071
                4 October 2012
                4 October 2012
                June 2013
                : 70
                : 12
                : 2059-2081
                Affiliations
                [ ]Program in Developmental and Stem Cell Biology, Department of Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto Medical Discovery Tower, East Tower, 101 College St., Toronto, ON M5G 1L7 Canada
                [ ]Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8 Canada
                [ ]Department of Surgery, University of Toronto, Toronto, ON M5S 1A8 Canada
                Article
                1152
                10.1007/s00018-012-1152-9
                3663196
                23052205
                1d150035-150e-4a20-b7ab-3996875ba20d
                © The Author(s) 2012
                History
                : 31 January 2012
                : 29 August 2012
                : 30 August 2012
                Categories
                Review
                Custom metadata
                © Springer Basel 2013

                Molecular biology
                wound healing,regeneration,skin,wnt,β-catenin,transforming growth factor β (tgf-β),notch,hedgehog

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