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      Distinct fibroblast lineages determine dermal architecture in skin development and repair

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          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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          Most cited references 32

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          Fibroblasts in cancer.

          Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.
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            Wound repair and regeneration.

            The repair of wounds is one of the most complex biological processes that occur during human life. After an injury, multiple biological pathways immediately become activated and are synchronized to respond. In human adults, the wound repair process commonly leads to a non-functioning mass of fibrotic tissue known as a scar. By contrast, early in gestation, injured fetal tissues can be completely recreated, without fibrosis, in a process resembling regeneration. Some organisms, however, retain the ability to regenerate tissue throughout adult life. Knowledge gained from studying such organisms might help to unlock latent regenerative pathways in humans, which would change medical practice as much as the introduction of antibiotics did in the twentieth century.
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              Wound healing--aiming for perfect skin regeneration.

               Tamara 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.

                Author and article information

                [1 ]Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge CB2 1QR, UK.
                [2 ]Department of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
                [3 ]Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
                [4 ]Institut Clinique de la Souris, Parc d’Innovation, 67404 Illkrich-Graffenstaden, Cedex, France
                [5 ]Centre for Stem Cells and Regenerative Medicine, King’s College London, 28 th floor, Tower Wing, Guy’s Hospital, London SE1 9RT, UK
                [6 ]Department of Physics, Cavendish Laboratory, University of Cambridge, CB3 0HE
                Author notes
                [* ]Correspondence and requests for materials should be addressed to ( fiona.watt@ ; +44 20 7188 5608).

                Author Contributions RRD and FMW designed the experiments, performed data analysis, interpreted the results, and wrote the manuscript. BML, EH, KK, ACFS, SRF, BDS and MC assisted in performing and designing experiments, analyzing data, and interpreting results. YH and GP generated the Dlk1CreERt transgenic mouse.

                1 November 2013
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                12 June 2014
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