Exogenous Smad3 accelerates wound healing in a rabbit dermal ulcer model.
Exogenous administration of transforming growth factor-beta (TGF-beta) improves wound healing by affecting cellular and molecular events involved in tissue repair. But mice with a deficiency of a key TGF-beta signaling intermediate, Smad3, paradoxically showed accelerated cutanenous wound healing, suggesting that endogenous Smad3 had inhibitory effect on cutaneous wound healing. Here we investigated the effect of exogenous expression of Smad3 in dermal fibroblasts on cutaneous wound healing. Subcutaneous injection of adenovirus-containing Smad3 complementary DNA (AdCMV-Smad3) targeting mainly dermal fibroblasts accelerated tissue repair following full-thickness dermal round wounds in rabbit ear as judged by the size of granulation tissue area, number of capillaries, and re-epithelialization rate of the wounds. Expressions of alpha-smooth muscle actin (alpha-SMA), vascular endothelial growth factor (VEGF), and fibroblast growth factor receptor were upregulated in the wounded area injected with AdCMV-Smad3. Consistent with the in vivo findings, overexpression of Smad3 induced alpha-SMA, VEGF, and TGF-beta1 expression and augmented chemotactic response in cultured dermal fibroblasts. Therefore, exogenous administration of Smad3 targeting dermal fibroblasts accelerated tissue repair in a rabbit dermal ulcer model by affecting fibroblast responses associated with wound healing. The results suggest that Smad3, when overexpressed in dermal fibroblasts, can promote wound healing.
Sumiyoshi
Koji
K
Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan.
Nakao
Atsuhito
A
Setoguchi
Yasuhiro
Y
Okumura
Ko
K
Ogawa
Hideoki
H
D000199:Actins / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D020405:Dermis / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D015870:Gene Expression; D015316:Genetic Therapy; D066298:In Vitro Techniques; D051379:Mice; D011817:Rabbits; D012883:Skin Ulcer / Q000473:pathology / Q000628:therapy*; D051900:Smad3 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D014945:Wound Healing
D000199:Actins; D004268:DNA-Binding Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A