TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair.
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 -beta1 (TGF-beta1) 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-beta1 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-beta1 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-beta1 on lymphatic endothelial cells (LECs) in vitro were evaluated. As a result, the wound repair with collagen gel significantly reduced the expression of TGF-beta1, decreased scarring/fibrosis, and significantly accelerated lymphatic regeneration. The addition of recombinant TGF-beta1 to the collagen gel negated these effects. The improved lymphatic regeneration secondary to TGF-beta1 inhibition was associated with increased infiltration and proliferation of LECs and macrophages. TGF-beta1 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-beta1 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-beta1 expression significantly accelerates lymphatic regeneration during wound healing. An increased TGF-beta1 expression inhibits LEC proliferation and function and promotes lymphatic fibrosis. These findings imply that the clinical interventions that diminish TGF-beta1 expression may be useful in promoting more rapid lymphatic regeneration.
Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Nicholas W
NW
Clavin
Tomer
T
Avraham
John
J
Fernandez
Sanjay V
SV
Daluvoy
Marc A
MA
Soares
Arif
A
Chaudhry
Babak J
BJ
Mehrara
D000279:Administration, Cutaneous; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002921:Cicatrix / Q000378:metabolism / Q000503:physiopathology; D003094:Collagen / Q000008:administration & dosage; D062109:Dermatologic Surgical Procedures; D004729:Endothelium, Lymphatic / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D005782:Gels; D008026:Ligation; D042583:Lymphangiogenesis / Q000187:drug effects; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D008209:Lymphedema / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013623:Tail; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects
D005782:Gels; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D003094:Collagen