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

Clavin NW, Avraham T, Fernandez J, Daluvoy SV, Soares MA, Chaudhry A, Mehrara BJ. TGF-beta(1) is a negative regulator of lymphatic regeneration during wound repair. Am J Physiol Heart Circ Physiol 295: H2113-H2127, 2008. First published October 10, 2008; doi: 10.1152/ajpheart.00879.2008.-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 -beta(1) (TGF-beta(1)) 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-beta(1) 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-beta(1) 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-beta(1) on lymphatic endothelial cells (LECs) in vitro were evaluated. As a result, the wound repair with collagen gel significantly reduced the expression of TGF-beta(1), decreased scarring/ fibrosis, and significantly accelerated lymphatic regeneration. The addition of recombinant TGF-beta(1) to the collagen gel negated these effects. The improved lymphatic regeneration secondary to TGF-beta(1) inhibition was associated with increased infiltration and proliferation of LECs and macrophages. TGF-beta(1) 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-beta(1) during wound repair resulted in lymphatic fibrosis and the coexpression of alpha-smooth muscle actin and lymphatic vessel endothelial receptor-1 in regenerated lymphatics. In conclusion, the inhibition of TGF-beta(1) expression significantly accelerates lymphatic regeneration during wound healing. An increased TGF-beta(1) expression inhibits LEC proliferation and function and promotes lymphatic fibrosis. These findings imply that the clinical interventions that diminish TGF-beta(1) expression may be useful in promoting more rapid lymphatic regeneration.