The roles of type VII collagen in wound healing and scar reduction

2014-10-20Dystrophic epidermolysis bullosa (DEB) is a family of rare inherited mechano-bullous disorders caused by mutations in the gene encoding for type VII collagen (C7), the major component of anchoring fibrils (AF). These mutations cause perturbations in AFs, structures that hold the outer epidermal layer of skin onto the inner dermal connective tissue layer. Without sufficient functioning AFs, the epidermis separates from the dermis. Children with DEB are born with skin fragility and continuous blistering of the skin in trauma-prone sites. Eventually, most of these children die from aggressive squamous cell carcinoma at the sites of chronic blistering and scarring. The C7 gene knockout mouse model recapitulates the clinical, genetic and ultrastructural features of human recessive DEB. ❧ We evaluated the feasibility of C7 based protein therapeutics via intradermal injection (ID) of recombinant human C7 (rC7) into DEB mice or topical application of rC7 onto skin wounds created onto normal mice or engrafted DEB mouse skin. With both administrations, we found that rC7 migrated and incorporated into the mouse’ basement membrane zone (BMZ), enhanced adherence of dermal epidermal junction, and reduced blistering formation. The most pivotal benefit of ID C7 is the prolonged life expectancy for DEB mice. Based on the preclinical studies, we conclude that protein based therapeutics may be feasible for the treatment of human patients with DEB. ❧ Moreover, the wounds treated with topical rC7 exhibited accelerated wound closure and less scar formation. Topical rC7 decreased the expression of pro-fibrogenic TGF-β2 and increased the expression of anti-fibrogenic TGF-β3, accompanied by the reduced expression of CTGF, fewer α-SMA positive myofibroblasts, and less deposition of collagen in the healed neodermis, consistent with less scar formation. In addition, we obtained skin and serum samples from DEB patients, and discovered that DEB patients display increased expression of pro-fibrotic TGF-β isoforms as well as markers associated with fibrosis. With siRNA knockdown C7 in normal fibroblasts and re-introduction of C7 to DEB patients’ cells, we confirmed that C7 loss is directly responsible for the up-regulated TGF-β signaling associated with fibrosis. These studies provided the first evidence of the potential use of topical C7 for accelerating scar-less wound healing. These findings suggest that C7 based protein therapeutics could be used for the treatments of DEB patients as well as accelerate wound healing with less scar formation in patients with chronic skin wounds