Postulated mechanism by which fibroblast therapy may ameliorate the blistering tendency in RDEB. (a) In normal skin, keratinocytes synthesize type VII collagen molecules (red), which assemble into anchoring fibrils. These fibrils entrap the interstitial collagen fibers in the dermis, securing the stable association at the dermal-epidermal junction. (b) In some patients with RDEB, there are only a few rudimentary anchoring fibrils, allowing formation of blisters below the lamina densa as a result of minor trauma. (c) Allogeneic fibroblasts injected directly into dermis elicit a subclinical immune reaction that leads to synthesis of heparin binding-EGF-like growth factor (HB-EGF), which upregulates the synthesis and assembly of patient’s own mutated type VII collagen. The increase in the rudimentary anchoring fibrils, which are partially functional, stabilizes the association of epidermis to the underlying dermis and ameliorates the blistering tendency. (Adapted from Uitto, 2011a).