KERATINOCYTE-SPECIFIC EXPRESSION OF HUMAN THROMBOMODULIN IN TRANSGENIC MICE - EFFECTS ON EPIDERMAL DIFFERENTIATION AND CUTANEOUS WOUND-HEALING

Background: Thrombomodulin is a cell-surface glycoprotein that regulat es coagulation and fibrinolysis. Expression of thrombomodulin by epide rmal keratinocytes is tightly regulated during squamous differentiatio n and cutaneous wound healing. Methods: To determine the consequences of overexpression of thrombomodulin on squamous differentiation and wo und healing in vivo, we expressed full-length human thrombomodulin in transgenic mice using the human keratin 14 promoter. Human thrombomodu lin was detected in keratinocytes of transgenic mice by immunohistoche mistry and protein C activation assays. Full-thickness cutaneous wound s were created on the dorsum of transgenic mice and nontransgenic litt ermates, and allowed to heal for up to 35 days. Results: Transgenic mi ce had normal viability and appeared healthy up to one year of age. In the skin, human thrombomodulin was expressed in basal and suprabasal keratinocytes, with variable expression in the outer root sheath of ha ir follicles. Thrombomodulin activity in neonatal epidermis was 2.5- t o 3-fold higher in transgenic mice than in nontransgenic littermates ( p < 0.01), In cutaneous wounds, human thrombomodulin was expressed in migrating neoepidermal keratinocytes, No differences in keratinocyte m igration or re-epithelialization were observed between transgenic and nontransgenic mice, but transgenic mice exhibited delayed collagen bun dle deposition within the wound matrix. Conclusions: These findings de monstrate that keratinocyte thrombomodulin supports activation of prot ein C, and that thrombomodulin activity in epidermis can be increased by keratinocyte-specific expression of human thrombomodulin in transge nic mice. Expression of human thrombomodulin in keratinocytes does not impair normal squamous differentiation or re-epithelialization of cut aneous wounds, but may modulate collagen reconstitution of the wound m atrix.