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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/H2113    most recent 00879.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Clavin, N. W. Articles by Mehrara, B. J. Search for Related Content PubMed PubMed Citation Articles by Clavin, N. W. Articles by Mehrara, B. J.

TGF-β₁ is a negative regulator of lymphatic regeneration during wound repair

Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

Submitted 8 August 2008 ; accepted in final form 3 October 2008

Although clinical studies have identified scarring/fibrosis as significant risk factors for lymphedema, the mechanisms by which lymphatic repair is impaired remain unknown. Transforming growth factor -β₁ (TGF-β₁) is a critical regulator of tissue fibrosis/scarring and may therefore also play a role in the regulation of lymphatic regeneration. The purpose of this study was therefore to assess the role of TGF-β₁ on scarring/fibrosis and lymphatic regeneration in a mouse tail model. Acute lymphedema was induced in mouse tails by full-thickness skin excision and lymphatic ligation. TGF-β₁ expression and scarring were modulated by repairing the wounds with or without a topical collagen gel. Lymphatic function and histological analyses were performed at various time points. Finally, the effects of TGF-β₁ on lymphatic endothelial cells (LECs) in vitro were evaluated. As a result, the wound repair with collagen gel significantly reduced the expression of TGF-β₁, decreased scarring/fibrosis, and significantly accelerated lymphatic regeneration. The addition of recombinant TGF-β₁ to the collagen gel negated these effects. The improved lymphatic regeneration secondary to TGF-β₁ inhibition was associated with increased infiltration and proliferation of LECs and macrophages. TGF-β₁ caused a dose-dependent significant decrease in cellular proliferation and tubule formation of isolated LECs without changes in the expression of VEGF-C/D. Finally, the increased expression of TGF-β₁ during wound repair resulted in lymphatic fibrosis and the coexpression of -smooth muscle actin and lymphatic vessel endothelial receptor-1 in regenerated lymphatics. In conclusion, the inhibition of TGF-β₁ expression significantly accelerates lymphatic regeneration during wound healing. An increased TGF-β₁ expression inhibits LEC proliferation and function and promotes lymphatic fibrosis. These findings imply that the clinical interventions that diminish TGF-β₁ expression may be useful in promoting more rapid lymphatic regeneration.

lymphangiogenesis; scar; lymphedema; vascular endothelial growth factor C; transforming growth factor-β₁; excisional wound healing; myofibroblast; fibrosis