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Inhibiting Scar Formation in Rat Wounds by Adenovirus-Mediated Overexpression of Truncated TGF-β Receptor II

Liu, Wei M.D., Ph.D.; Chua, Chekhau M.D.; Wu, Xiaoli M.D.; Wang, Danru M.D., Ph.D.; Ying, Demin B.S.; Cui, Lei M.D., Ph.D.; Cao, Yilin M.D., Ph.D.

Plastic and Reconstructive Surgery: March 2005 - Volume 115 - Issue 3 - p 860-870
doi: 10.1097/01.PRS.0000153037.12900.45

The purpose of this study was to explore the possibility of inhibiting wound scarring by blocking TGF-β signaling of wound cells by means of a gene therapy approach. Normal dermal fibroblasts were infected in vitro either with recombinant adenovirus encoding a truncated TGF-β receptor II (Ad-tTGF-βRII) or with β-galactosidase adenovirus (Ad-β-gal). TGF-β1 gene expression in infected fibroblasts was analyzed by Northern blot. In vivo, 1×109 plaque-forming units of Ad-tTGF-βRII were intradermally injected into the dorsal skin of 10-day-old newborn Sprague-Dawley rats (n = 10). For gene therapy, 1×109 plaque-forming units of Ad-tTGF-βRII viruses were injected intradermally at the right side dorsal skin of another set of same aged Sprague-Dawley rats as the experimental group (n = 15). In the control group, 1×109 plaque-forming units of Ad-β-gal (n = 11) or the same volume of saline (n = 4) was injected at the left side skin of the same rats. A 5-mm-long full-thickness incisional wound was created at the injection sites of each rat 2 days after injection. Wound tissues were harvested at day 3 (n = 2), day 7 (n = 2), and day 14 (n = 11) after wounding for histological analysis. Scar area of wound tissues harvested at day 14 was quantitatively analyzed. The results showed that TGF-β1 gene expression was markedly down-regulated in Ad-tTGF-βRII infected fibroblasts compared with Ad-β-gal infected cells. In vivo, adenovirus-mediated transgene expression in rat skin reached a peak level at day 2 after injection and the expression gradually decreased afterward. Inhibited inflammatory reaction was also observed in the treated wounds with significantly reduced inflammatory cells (p < 0.05). Moreover, in all 11 rats, the experimental wound at day 14 had much less scarring than its control wound of the same rat, with an average of 49 percent reduction of the scar area (p < 0.05). Furthermore, more panniculus muscles were repaired in the experimental wounds (nine of 11) than in the control wounds (two of 11) (p < 0.05). These results indicate that gene therapy by targeting wound TGF-β can effectively inhibit wound scarring and may potentially be applied to clinical scar treatment.

Shanghai, P.R. China

From the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Second Medical University, Shanghai Institute of Plastic and Reconstructive Surgery, Shanghai Tissue Engineering Center.

Received for publication April 24, 2003; revised April 5, 2004.

Presented at the 47th Annual Meeting of the Plastic Surgery Research Council, in Boston, Massachusetts, April 17 to 20, 2002, and at the 2002 Joint Conference of the Wound Healing Society and the European Tissue Repair Society, in Baltimore, Maryland, May 28 to June 1, 2002.

Wei Liu and Chekhau Chua are co-first authors of this article.

Wei Liu, M.D., Ph.D. Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, 639 Zhi Zao Ju Road, Shanghai 200011, P.R.China,

©2005American Society of Plastic Surgeons