Subject(s)
Exanthema/etiology , Zinc/deficiency , Diagnosis, Differential , Exanthema/diagnosis , Exanthema/drug therapy , Face , Humans , Infant , Male , Zinc/blood , Zinc/therapeutic useSubject(s)
Basal Cell Nevus Syndrome/prevention & control , Neoplasms, Radiation-Induced/prevention & control , Radiation Protection/methods , Skin Neoplasms/prevention & control , Sunlight/adverse effects , Vitamin D Deficiency/etiology , Basal Cell Nevus Syndrome/diagnosis , Basal Cell Nevus Syndrome/etiology , Biomarkers/blood , Cholecalciferol/administration & dosage , Dietary Supplements , Fractures, Bone/etiology , Humans , Iatrogenic Disease , Male , Middle Aged , Neoplasms, Radiation-Induced/diagnosis , Neoplasms, Radiation-Induced/etiology , Protective Clothing/adverse effects , Risk Factors , Skin Neoplasms/diagnosis , Skin Neoplasms/etiology , Sunscreening Agents/administration & dosage , Sunscreening Agents/adverse effects , Time Factors , Treatment Outcome , Vitamin D/analogs & derivatives , Vitamin D/blood , Vitamin D Deficiency/blood , Vitamin D Deficiency/diagnosis , Vitamin D Deficiency/drug therapyABSTRACT
Here, we report on the first systematic long-term study of fibroblast therapy in a mouse model for recessive dystrophic epidermolysis bullosa (RDEB), a severe skin-blistering disorder caused by loss-of-function of collagen VII. Intradermal injection of wild-type (WT) fibroblasts in >50 mice increased the collagen VII content at the dermal-epidermal junction 3.5- to 4.7-fold. Although the active biosynthesis lasted <28 days, collagen VII remained stable and dramatically improved skin integrity and resistance to mechanical forces for at least 100 days, as measured with a digital 3D-skin sensor for shear forces. Experiments using species-specific antibodies, collagen VII-deficient fibroblasts, gene expression analyses, and cytokine arrays demonstrated that the injected fibroblasts are the major source of newly deposited collagen VII. Apart from transitory mild inflammation, no adverse effects were observed. The cells remained within an area Subject(s)
Cell- and Tissue-Based Therapy/methods
, Collagen Type VII/metabolism
, Epidermolysis Bullosa Dystrophica/therapy
, Fibroblasts/physiology
, Skin/pathology
, Animals
, Animals, Newborn
, Blotting, Western
, Cells, Cultured
, Epidermolysis Bullosa Dystrophica/metabolism
, Epidermolysis Bullosa Dystrophica/pathology
, Fibroblasts/metabolism
, Fibroblasts/ultrastructure
, Flow Cytometry
, Humans
, In Situ Nick-End Labeling
, Mice
, Mice, Transgenic
, Microscopy, Electron, Transmission
, Reverse Transcriptase Polymerase Chain Reaction
, Skin/metabolism
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.
