Role of activin and follistatin in wound healing after cutaneous injury in the mouse

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Wound healing is an orchestrated process consisting of three overlapping phases: inflammation, restoration and maturation. The alteration of any of these processes can alter the final outcome, leading either to a non-healing wound or to excessive scarring. Activin A, a member of the transforming growth factor (TGF)-beta family, is one of the principal factors involved during wound healing and, together with follistatin, a modulator of activin actions, regulates skin homeostasis and skin repair. Sex hormones also influence wound healing; males are more predisposed to develop non-healing wounds than females. This thesis aimed to evaluate whether testosterone is able to modulate the wound healing actions of activin and whether follistatin can be used to decrease the bioactivity of activin and enhance the healing process. Intact and castrated male mice received two linear 1-cm long incisions and their wounds were evaluated at days 3, 5, 7 and 14 post-wounding. Serum and skin levels of activin A, follistatin and the pro-inflammatory cytokines IL-6 and TNF-α were evaluated. Wounding of the skin caused significant increases in activin A and follistatin skin levels; however, the increases in these proteins were higher in the presence of testosterone, especially during the inflammatory phase. The increase in activin A was correlated with increased levels of IL-6 in skin in the presence of testosterone; under these conditions, males healed their wounds with a disorganised structure of the dermis that was indicative of fibrotic tissue. The subcutaneous administration of follistatin (0.1 µg/injection) to the wounds of male mice decreased activin A and IL-6 skin levels, decreased the number of leukocytes at the wound site, and decreased the area of the wound. In conclusion, testosterone promoted an increase in activin A skin levels following wounding, with an enhanced inflammatory response, delaying wound closure and stimulating the development of scarring tissue. This response was avoided by the administration of follistatin, indicating that the actions of testosterone on wound healing in males are likely to be achieved through activin A.