Department of Dermatology, University of Southern California, Los Angeles, California, USA.
Mol Ther. 2013 Jul;21(7):1335-44. doi: 10.1038/mt.2013.87. Epub 2013 May 14.
Patients with recessive dystrophic epidermolysis bullosa (RDEB) have incurable skin fragility, blistering, and skin wounds due to mutations in the gene that codes for type VII collagen (C7) that mediates dermal-epidermal adherence in human skin. In this study, we evaluated if topically applied human recombinant C7 (rC7) could restore C7 at the dermal-epidermal junction (DEJ) and enhance wound healing. We found that rC7 applied topically onto murine skin wounds stably incorporated into the newly formed DEJ of healed wounds and accelerated wound closure by increasing re-epithelialization. Topical rC7 decreased the expression of fibrogenic transforming growth factor-β2 (TGF-β2) and increased the expression of anti-fibrogenic TGF-β3. These were accompanied by the reduced expression of connective tissue growth factor, fewer α smooth muscle actin (α-SMA)-positive myofibroblasts, and less deposition of collagen in the healed neodermis, consistent with less scar formation. In addition, using a mouse model in which skin from C7 knock out mice was grafted onto immunodeficient mice, we showed that applying rC7 onto RDEB grafts with wounds restored C7 and anchoring fibrils (AFs) at the DEJ of the grafts and corrected the dermal-epidermal separation. The topical application of rC7 may be useful for treating patients with RDEB and patients who have chronic skin wounds.
隐性营养不良型大疱性表皮松解症（RDEB）患者由于编码 VII 型胶原（C7）的基因突变，导致皮肤脆弱、起泡和皮肤伤口，而 C7 介导了人类皮肤的真皮-表皮黏附。在这项研究中，我们评估了局部应用重组人 C7（rC7）是否可以恢复 C7 在真皮-表皮交界处（DEJ）的位置，并促进伤口愈合。我们发现，rC7 局部应用于小鼠皮肤伤口，可稳定地整合到愈合伤口的新形成的 DEJ 中，并通过增加再上皮化加速伤口闭合。局部 rC7 降低了纤维生成转化生长因子-β2（TGF-β2）的表达，并增加了抗纤维化 TGF-β3 的表达。这伴随着结缔组织生长因子表达减少，α平滑肌肌动蛋白（α-SMA）阳性肌成纤维细胞减少，以及新形成的真皮中胶原沉积减少，与疤痕形成减少一致。此外，我们使用 C7 基因敲除小鼠的皮肤移植到免疫缺陷小鼠的模型中，表明在 RDEB 移植物上有伤口的情况下，局部应用 rC7 可以恢复 C7 和锚定纤维（AFs）在移植物的 DEJ 上，并纠正真皮-表皮分离。rC7 的局部应用可能对治疗 RDEB 患者和患有慢性皮肤伤口的患者有用。
