Healing of burn wounds in transgenic mice overexpressing transforming growth factor-beta 1 in the epidermis.
Transforming growth factor-beta (TGF-beta) isoforms are multifunctional cytokines that play an important role in wound healing. Transgenic mice overexpressing TGF-beta in the skin under control of epidermal-specific promoters have provided models to study the effects of increased TGF-beta on epidermal cell growth and cutaneous wound repair. To date, most of these studies used transgenic mice that overexpress active TGF-beta in the skin by modulating the latency-associated-peptide to prevent its association with active TGF-beta. The present study is the first to use transgenic mice that overexpress the natural form of latent TGF-beta 1 in the epidermis, driven by the keratin 14 gene promoter to investigate the effects of locally elevated TGF-beta 1 on the healing of partial-thickness burn wounds made on the back of the mice using a CO(2) laser. Using this model, we demonstrated activation of latent TGF-beta after wounding and determined the phenotypes of burn wound healing. We found that introduction of the latent TGF-beta1 gene into keratinocytes markedly increases the release and activation of TGF-beta after burn injury. Elevated local TGF-beta significantly inhibited wound re-epithelialization in heterozygous (42% closed versus 92% in controls, P < 0.05) and homozygous (25% versus 92%, P < 0.01) animals at day 12 after wounding. Interestingly, expression of type I collagen mRNA and hydroxyproline significantly increased in the wounds of transgenic mice, probably as a result of a paracrine effect of the transgene.
Yang
L
L
Department of Surgery, Division of Plastic and Reconstructive Surgery, Wound Healing Research Group, University of Alberta, Edmonton, Alberta, Canada.
Chan
T
T
Demare
J
J
Iwashina
T
T
Ghahary
A
A
Scott
P G
PG
Tredget
E E
EE
D000818:Animals; D002056:Burns / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology; D024042:Collagen Type I / Q000235:genetics; D004817:Epidermis / Q000254:growth & development* / Q000293:injuries / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D053547:Keratin-14; D015603:Keratinocytes / Q000166:cytology; D007633:Keratins / Q000235:genetics; D007834:Lasers / Q000009:adverse effects; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000235:genetics; D012867:Skin / Q000737:chemistry / Q000293:injuries / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D019076:Transgenes / Q000235:genetics; D014945:Wound Healing
D024042:Collagen Type I; C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007633:Keratins; D006909:Hydroxyproline