A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy
Anja Fritsch, … , Reinhard Fässler, Leena Bruckner-Tuderman
Anja Fritsch, … , Reinhard Fässler, Leena Bruckner-Tuderman
Published April 1, 2008
Citation Information: J Clin Invest. 2008;118(5):1669-1679. https://doi.org/10.1172/JCI34292.
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Research Article Dermatology

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

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-β1–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.

Authors

Anja Fritsch, Stefan Loeckermann, Johannes S. Kern, Attila Braun, Michael R. Bösl, Thorsten A. Bley, Hauke Schumann, Dominik von Elverfeldt, Dominik Paul, Miriam Erlacher, Dirk Berens von Rautenfeld, Ingrid Hausser, Reinhard Fässler, Leena Bruckner-Tuderman

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Figure 5

Mitten deformities in the extremities of the Col7a1flNeo/flNeo mice closely resemble severe human RDEB.

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Mitten deformities in the extremities of the Col7a1flNeo/flNeo mice clos...
(A–C) Hands in human RDEB patients at 2.5 years (A), 6.5 years (B), and 7.5 years of age (C). (D–G) Fore paws of Col7a1flNeo/flNeo mice were documented at 17 days (D), 60 days (E), and 80 days of age (F and G). The clinical phenotypes in RDEB patients and in Col7a1flNeo/flNeo mice developed in a similar manner.