TGF-{beta}1 is a negative regulator of lymphatic regeneration during wound repair.

[lymphedemapeople]

TGF-{beta}1 is a negative regulator of lymphatic regeneration during
wound repair.

Am J Physiol Heart Circ Physiol. 2008 Oct 10

Clavin NW, Avraham T, Fernandez JG, Daluvoy SV, Soares M, Chaudhry A,
Mehrara BJ.
Memorial Sloan-Kettering Cancer Center.

Introduction: Although clinical studies have identified scarring/
fibrosis as significant risk factors for lymphedema, the mechanisms by
which lymphatic repair is impaired remain unknown. 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.

Methods: Acute lymphedema was induced in mouse tails by full thickness
skin excision and lymphatic ligation. TGF-beta1 expression and
scarring were modulated by repairing wounds with or without topical
collagen gel. Lymphatic function and histologic analyses were
performed at various time points. Finally, the effects of TGF-beta1 on
lymphatic endothelial cell (LEC) in vitro were evaluated. Results:
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. 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, increased expression of TGF-beta1 during wound repair
resulted in lymphatic fibrosis and co-expression of alpha-SMA and
LYVE-1 in regenerated lymphatics.

Conclusions: Inhibition of TGF-beta1 expression significantly
accelerates lymphatic regeneration during wound healing. Increased TGF-
beta1 expression inhibits LEC proliferation and function, and promotes
lymphatic fibrosis. These findings imply that clinical interventions
that diminish TGF-beta1 expression may be useful in promoting more
rapid lymphatic regeneration.

Key words: lymphangiogenesis, scar, lymphedema, wound healing.

http://ajpheart.physiology.org/cgi/content/abstract/00879.2008v1