Facilitated Wound Healing by Activation of the Transglutaminase 1 Gene

Abstract

Transglutaminase 1 (TGase 1) is a Ca(2+)-dependent enzyme which catalyzes epsilon-(gamma-glutamyl)lysine cross-linking of substrate proteins such as involucrin and loricrin to generate the cornified envelope at the cell periphery of the stratum corneum. We have shown that disruption of the TGase 1 gene in mice results in neonatal lethality, absence of the cornified envelope, and impaired skin barrier function. Based on the importance of TGase 1 in epidermal morphogenesis, we have now assessed its role in wound healing. In neonatal mouse skin, TGase 1 mRNA as well as keratin 6alpha was induced in the epidermis at the wound edges as early as 2 hours after injury and that expression continued in the migrating epidermis until completion of re-epithelialization. The TGase 1 enzyme co-localized on the plasma membrane of migrating keratinocytes with involucrin, but not with loricrin, which suggests the premature assembly of the cornified envelope. Similar injuries to TGase 1 knockout mouse skins grafted on athymic nude mice showed substantial delays in wound healing concomitant with sustained K6alpha mRNA induction. From these results, we suggest that activation of the TGase 1gene is essential for facilitated repair of skin injury.

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

“…Similar defective barrier functions were noted in stratified squamous epithelia of the tongue and forestomach, whereas epithelial cells and adherens junctions in lung, liver, and kidney were unaffected (154). Compared with control grafts from wild-type mice, skin from TG1 Ϫ/Ϫ neonates grafted onto nude mice showed a substantial delay in epidermal regeneration following a full-thickness 10-mm linear incision, thereby demonstrating the importance of TG1 in skin wound healing (123).…”

“…282). TG1 is important for cutaneous regeneration (123). Both TG2 and FXIII-A appear to be involved in tissue injury/remodeling, although their precise contributions to the various different stages of injury/remodeling have not yet been fully characterized.…”

Development of ichthyosiform skin compensates for defective permeability barrier function in mice lacking transglutaminase 1

“…Indeed, TGase 1 -/-mouse skin that matures after transplantation to nude mice reveals an ichthyosiform appearance with thickening epidermis, severe hyperkeratosis, and alopecia. We have recently reported a substantial delay in wound healing in the mature grafted TGase 1 -/-skin (35). In that report, however, we did not characterize the dramatic remodeling of the phenotype that occurs after birth and no evidence was reported about its biological or clinical meaning.…”

Development of ichthyosiform skin compensates for defective permeability barrier function in mice lacking transglutaminase 1

“…The rabbit polyclonal anti-mouse pro-liferating cell nuclear antigen (PCNA) antibody used as a primary antibody was purchased from Sigma Chemical Co. (St. Louis, Missouri, USA). Immunofluorescence for involucrin and loricrin was performed as described previously using rabbit polyclonal mouse loricrin and mouse involucrin antibodies (Covance Research Products Inc., Richmond, California, USA) (35).…”