Transforming growth factor beta (TGF-β) induces fibrosis in a fetal wound model

The adult cellular response to tissue injury is characterized by acute inflammation followed eventually by fibroblast proliferation and collagen synthesis. Fetal tissue responses to injury differ markedly from those of the adult; an early acute inflammatory response is absent, few fibroblasts participate, and no collagen is deposited. The object of the present study was to analyze the effects of transforming growth factor beta (TGF-β), an important regulatory molecule in adult healing events, on the fetal tissue response following wounding. Fetal cellular and extracellular matrix responses to injury were evaluated by placing subcutaneous wound implants containing TGF-β (0.01 to 10 ng) in fetal rabbits at 24 days gestation (term =31 days). Histologic responses one to seven days later were compared with fetal and adult control implants without TGF-β. The histology of the adult implant was characterized by an early acute inflammatory response: by day 7 fibroblasts and collagen were predominant. In contrast, control implants removed from fetal rabbits had no histologic evidence of acute inflammation or fibroblast penetration and no collagen was deposited. When implants containing 1.0 ng TGF-β were removed from fetal rabbits at seven days, a grossly fibrotic reaction was observed: histology confirmed marked fibroblast penetration with collagen deposition. Fetal implants containing 0.01 ng or 10 ng TGF-β showed few fibroblasts but had increased numbers of inflammatory cells compared with controls. These observations demonstrate that the fetal response becomes adultlike with fibroblast proliferation and collagen accumulation when TGF-β is added, thus documenting the responsiveness of the fetal system to adult repair signals. Such responsiveness thus suggests a critical difference in the fetal wound environment. Fetal repair may proceed in the absence of trophic factors like TGF-β, thus accounting for optimal “healing” in the absence of excessive fibrosis.