Mechanisms of wound reepithelialization: hints from a tissue-engineered reconstructed skin to long-standing questions

Wound closure of epithelial tissues must occur efficiently to restore rapid ly their barrier function. We have developed a tissue-engineered wound-heal ing model composed of human skin keratinocytes and fibroblasts to better un derstand the mechanisms of reepithelialization. It allowed us to quantify t he reepithelialization rate, which was significantly accelerated in the pre sence of fibrin or platelet-rich plasma. The reepithelialization of these 6 mm excisional wounds required the contribution of keratinocyte proliferati on, migration, stratification, and differentiation. The epidermis regenerat ed progressively from the surrounding wound margins. After 3 days, the neoe pidermis showed a complete spectrum of changes. Near the wound margin, the differentiation of the neoepidermis (keratins 1/10, filaggrin, and loricrin ) and regeneration of the dermoepidermal junction (laminin 5 and collagen I V) were more advanced than toward the wound center, where the proliferative index was significantly increased. The spatial distribution of keratinocyt es distinguished by particular features suggests two complementary mechanis ms of reepithelialization: 1) the passive displacement of the superficial l ayers near the wound margin that would rapidly regenerate a barrier functio n and 2) the crawling of keratinocytes over each other at the tip of the pr ogressing neoepidermis. Therefore, this study brings a new perspective to l ong-standing questions concerning wound reepithelialization.