TGF-β in wound repair and scarring

Wound healing is a multi-step process which is the result of complex interactions of cells present in the injured tissue with cellular and soluble blood constituents (1). These interactions are governed by the action of growth factors, chemokines, and hormones. Cellular responses as well as the action of soluble mediators are modulated by the extracellular matrix (ECM) present in the wound area. Wound repair proceeds through a sequence of different stages, each of them being fundamentally influenced by the TGF-β family members, TGF-β1, 2, 3, or activin (2-4). Among the first responses to injury are activation of platelets and the initiation of blood coagulation, whereby platelets are a major source of TGF-β1 in the early stages of wound repair (5, 6). The release and activation of platelet TGF-β1 probably contributes to the initiation of early cellular responses, such as the chemotactic recruitment of inflammatory cells (7) and new blood vessels (8) into the wound area. In contrast, TGF-β1 delays re-epithelialization when added to organotypic cultures in vitro (9) or when overexpressed in the epidermis in vivo (10). This inhibitory effect of TGF-β signaling in keratinocytes has been confirmed in vivo by transgenic studies demonstrating accelerated re-epithelialization in mice deficient in TGF-β1 (11), in the signaling keratinocyte type II TGF-β receptor (12), or in the intracellular TGF-β signal transducer, Smad3 (13). At later stages of normal wound repair, TGF-β1 is a major inducer of connective tissue production and myofibroblast activity. Consequently, TGF-β1 activity promotes wound contraction and enhances wound breaking strength (14). In addition, TGF-β1 stimulates scar formation and tissue remodeling and may also be involved in pathologic healing responses such as hypertrophic scarring and fibrosis (15, 16). Impaired wound healing states (e.g. venous and diabetic ulcers or glucocorticoid-induced wound healing defects) are characterized by reduced expression of TGF-β1 and the type II © 2004 Schattauer GmbH, Stuttgart