Altered TGF‐β signaling in fetal fibroblasts: What is known about the underlying mechanisms?

Scarless wound healing is a unique and intrinsic capacity of the fetal skin that is not fully understood. Further insight into the underlying mechanisms of fetal wound healing may lead to new therapeutic approaches promoting adult scarless wound healing. Differences between fetal and adult wound healing are found in the extracellular matrix, the inflammatory reaction and the levels of growth factors present in the wound. This review focuses specifically on transforming growth factor β (TGF-β), as this growth factor is prominently involved in wound healing and fibroblast-to-myofibroblast differentiation. Although fetal fibroblasts do respond to TGF-β, they lack a proliferative and a contractile response and display short-lived myofibroblast differentiation, autocrine response, and collagen up-regulation in comparison with adult fibroblasts. Curiously, prolonged TGF-β activation is associated with fibrosis, and therefore, this short-lived response in fetal fibroblasts might contribute to scarless healing. This review gives an overview of the current knowledge on TGF-β signaling and the intracellular TGF-β signaling pathway in fetal fibroblasts. Furthermore, this review also describes the various components that regulate the cellular TGF-β response and hypothesizes about the possible roles these components might play in the altered response of fetal fibroblasts to TGF-β.