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      Impaired Epidermal to Dendritic T Cell Signaling Slows Wound Repair in Aged Skin

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          Abstract

          <p id="P1">Aged skin heals wounds poorly, increasing susceptibility to infections. Restoring homeostasis after wounding requires the coordinated actions of epidermal and immune cells. Here we find that both intrinsic defects and communication with immune cells are impaired in aged keratinocytes, diminishing their efficiency in restoring the skin barrier after wounding. At the wound-edge, aged keratinocytes display reduced proliferation and migration. They also exhibit a dampened ability to transcriptionally activate epithelial-immune crosstalk regulators, including a failure to properly activate/maintain dendritic epithelial T-cells (DETCs), which promote re-epithelialization following injury. Probing mechanism, we find that aged keratinocytes near the wound edge don’t efficiently up-regulate <i>Skints</i> or activate STAT3. Notably, when epidermal <i>Stat3, Skints</i> or DETCs are silenced in young skin, re-epithelialization following wounding is perturbed. These findings underscore epithelial-immune crosstalk perturbations in general, and <i>Skints</i> in particular, as critical mediators in the age-related decline in wound-repair. </p><p id="P2">Progressive loss of communication between epithelial and immune cells in the skin underlies the slow down in wound healing associated with aging. </p><p id="P3"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/db978228-cf16-4b94-a672-b5d3901ee96e/PubMedCentral/image/nihms827525u1.jpg"/> </div> </p>

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          Most cited references25

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          Stem cell aging: mechanisms, regulators and therapeutic opportunities.

          Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic 'memory' that is indelibly written or one that can be reset.
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            Aging and wound healing.

            Impaired wound healing in the elderly presents a major clinical and economic problem. With the aging population growing in both number and percentage, the importance of understanding the mechanisms underlying age-related impairments in healing is increased. Normal skin exhibits characteristic changes with age that have implications for wound healing. Additionally, the process of wound healing is altered in aged individuals. Although historically healing in the aged was considered defective, there is now consensus that healing in the elderly is delayed but the final result is qualitatively similar to that in young subjects.
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              Gammadelta T cells and the lymphoid stress-surveillance response.

              The investigation of gammadelta T cells has identified a rapid lymphoid stress-surveillance response to microbial and nonmicrobial tissue perturbation. In addition to providing local protection, this response provides an immediate source of cytokines, chemokines, and other functions that can substantially affect downstream, adaptive immunity. Recent studies have identified striking mechanisms by which gammadelta cells meet the requirements of stress surveillance. For example, high response frequencies can reflect a unique nature of antigen engagement by the T cell receptor (TCR), developmental focusing of the repertoire by selection events, or the use of nonclonotypic receptors to initiate responses. Likewise, rapid functional deployment can be facilitated by the preprogramming of gammadelta cells during development. Additionally, gammadelta cells can directly influence adaptive immunity by functioning as antigen-presenting cells. With lymphoid stress surveillance likely to underpin numerous aspects of inflammation, tumor immunology, infectious disease, and autoimmunity, this perspective considers its properties and its emerging potential for clinical manipulation.
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                Author and article information

                Journal
                Cell
                Cell
                Elsevier BV
                00928674
                November 2016
                November 2016
                : 167
                : 5
                : 1323-1338.e14
                Article
                10.1016/j.cell.2016.10.052
                5364946
                27863246
                06f74551-2984-4ece-805c-f91451d75813
                © 2016
                History

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