A model of scarless human fetal wound repair is deficient in transforming growth factor beta

Abstract

Human fetal skin heals via scarless regeneration, whereas adult skin heals with scar. Scarless repair may reflect a distinct cytokine milieu. We studied the role of the cytokine transforming growth factor beta (TGFβ) using an established model of scarless human fetal skin repair in which human fetal skin is transplanted into a subcutaneous pocket on the flank of an adult nude mouse. In this model, wounded 16-week-gestation human fetal skin heals without scar, whereas wounded adult skin heals with scar. Seven days after transplantation, incisional wounds were made in the skin grafts. In the first phase of the study, wounds were harvested from 1 hour to 4 weeks postwounding, and immunohistochemistry was performed for TGFβ (isoform nonspecific), TGFβ 1, and TGFβ 2. Scarfree wounds in the fetal skin grafts did not show TGFβ staining. In contrast, wounds in adult grafts that heal with scar demonstrated isoform nonspecific TGFβ staining from 6 hours through 21 days, TGFβ 1 from 6 hours through 21 days, and TGFβ 2 from 12 hours through 7 days. In the second phase of the study, a slow-release disk with 0.01, 0.1, 1.0, or 10 μg of TGFβ 1 was placed beneath the fetal skin graft at the time of wounding. Fourteen days postwounding, there was marked scarring in the fetal grafts treated with TGFβ 1, and the size of the scar was proportional to the amount of TGFβ 1 applied. The relative lack of TGFβ, a cytokine known to promote fibrosis, may be one reason why the fetus heals by regeneration rather than scarring. In contrast, the fibrosis characteristic of postnatal wound repair may be associated with an excess of TGFβ. These findings suggest that anti-TGFβ therapeutic strategies may ameliorate scar formation in children and adults.