Hypertrophic
scarring is a skin disorder characterized by persistent
inflammation and
fibrosis that may occur after wounding or thermal injury. Altered production of
cytokines and
growth factors, such as
TGF-beta, play an important role in this process.
Activin A, a member of the
TGF-beta family, shares the same intra-cellular Smad signalling pathway with
TGF-beta, but binds to its own specific transmembrane receptors and to
follistatin, a secreted
protein that inhibits
activin by sequestration. Recent studies provide evidences of a novel role of
activin A in inflammatory and repair processes. The aim of this study was to evaluate the importance of
activin A and
follistatin expression in the different phases of
scar evolution. Immunostaining of sections obtained from active phase
hypertrophic scars (AHS) revealed the presence of a high number of alpha-SMA(+) myofibroblasts and
DC-SIGN(+) dendritic cells coexpressing
activin A. Ex-vivo AHS fibroblasts produced more
activin and less
follistatin than normal skin or remission phase
hypertrophic scar (HS) fibroblasts, both in basal conditions and upon TGF-betas stimulation. We demonstrate that fibroblasts do express
activin receptors, and that this expression is not affected by TGF-betas. Treatment of HS fibroblasts with
activin A induced Akt phosphorylation, promoted cell proliferation, and enhanced alpha-SMA and
type I collagen expression.
Follistatin reduced proliferation and suppressed
activin-induced
collagen expression. These results indicate that the
activin/
follistatin interplay has a role in HS formation and evolution. The impact of these observations on the understanding of wound healing and on the identification of new therapeutic targets is discussed.