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A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy.

The Journal of clinical investigation

Cells, Cultured, Animals, Collagen Type VII, genetics, metabolism, Disease Models, Animal, Epidermolysis Bullosa Dystrophica, physiopathology, therapy, Female, Fibroblasts, cytology, physiology, Foot Deformities, Congenital, Forelimb, abnormalities, Hand Deformities, Congenital, Humans, Male, Malnutrition, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, RNA Splicing, Skin, anatomy & histology, pathology

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      Abstract

      Dystrophic epidermolysis bullosa (DEB) is a severe skin fragility disorder associated with trauma-induced blistering, progressive soft tissue scarring, and increased risk of skin cancer. DEB is caused by mutations in type VII collagen. In this study, we describe the generation of a collagen VII hypomorphic mouse that serves as an immunocompetent animal model for DEB. These mice expressed collagen VII at about 10% of normal levels, and their phenotype closely resembled characteristics of severe human DEB, including mucocutaneous blistering, nail dystrophy, and mitten deformities of the extremities. The oral blistering experienced by these mice resulted in growth retardation, and repeated blistering led to excessive induction of tissue repair, causing TGF-beta1-mediated contractile fibrosis generated by myofibroblasts and pseudosyndactyly in the extremities. Intradermal injection of WT fibroblasts resulted in neodeposition of collagen VII and functional restoration of the dermal-epidermal junction. Treated areas were also resistant to induced frictional stress. In contrast, untreated areas of the same mouse showed dermal-epidermal separation following induced stress. These data demonstrate that fibroblast-based treatment can be used to treat DEB in a mouse model and suggest that this approach may be effective in the development of clinical therapeutic regimens for patients with DEB.

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      Journal
      2276400
      10.1172/JCI34292
      18382769

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