Imbalance between activin A and follistatin drives postburn hypertrophic scar formation in human skin.
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.
Fumagalli
Mara
M
Department of Plastic Surgery and Burn Unit Skin Bank, CTO Hospital, Torino, Italy.
Musso
Tiziana
T
Vermi
William
W
Scutera
Sara
S
Daniele
Roberta
R
Alotto
Daniela
D
Cambieri
Irene
I
Ostorero
Alessia
A
Gentili
Francesca
F
Caposio
Patrizia
P
Zucca
Mario
M
Sozzani
Silvano
S
Stella
Maurizio
M
Castagnoli
Carlotta
C
D000199:Actins / Q000378:metabolism; D029404:Activin Receptors / Q000378:metabolism; D028341:Activins / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002056:Burns / Q000150:complications / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D017439:Cicatrix, Hypertrophic / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000502:physiology; D038681:Follistatin / Q000378:metabolism*; D006801:Humans; D007118:Immunoassay; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
D000199:Actins; D038681:Follistatin; D053773:Transforming Growth Factor beta1; C422405:activin A; D028341:Activins; D029404:Activin Receptors