Fibroblasts, myofibroblasts, and wound contraction

clinical case reconstructed by Guido Majno (1975) from the Hippocratic records describes a wrestler who visits the iatreion (out-patient clinic) to be treated for a shoulder dislocation. With less invasive procedures no longer working to tighten the dislocation, the clinic adopts the drastic measure of inducing wound contraction by poking a hot needle through the skin of the armpit, and "in this way the cavity, into which the humerous is mostly displaced, is best scarred over and cut off" In Greek medicine circa 400 B.C.E., familiarity with wound contraction after burn injury already was commonplace. Closure of cutaneous wounds involves three processes: epithelization, connective tissue deposition, and contraction. The contribution of each process varies according to the type of wound. In general, epithelization results in resurfacing of the wound; connective tissue deposition results in replacement of damaged dermis; and contraction brings the margins of open wounds together (Peacock, 1984; Clark, 1988; Mast, 1992). In mammals with loose skin (meaning loosely attached to the underlying tissue layer), wound contraction leads to wound closure with little scarring or loss of function. In humans, whose skin is more firmly attached to underlying tissues, the consequences of contraction are less beneficial, ranging from minimal cosmetic scar in some cases to loss of joint motion or major body deformation in others. Consequently, a distinction has been made between contraction as a normal process of wound closure, and contracture as the abnormal result of the contraction process where signifcant scarring or loss of function occurs (Hunt and Dunphy, 1979). The pathologic consequences of tissue contraction include a variety of conditions ranging from contracture of the fibrous capsule surrounding breast implants to constricture of hollow organs (e.g., the esophagus) after injury (Skalli and Gabbiani, 1988; Rudolph et al., 1992). In contemporary cell biology, research on wound contraction focuses on the wound fibroblast. Skin fibroblasts normally are sessile and quiescent, but shortly after cutaneous wounding, they become activated. Activated fibroblasts migrate to the fibronectin-fibrin wound interface, proliferate, and synthesize a new collagen-containing matrix called granulation tissue. Around the same time, wound contraction begins. Once the wound defect is replaced, the expanded fibroblast population stops dividing and regresses and extracellular matrix remodeling commences (Peacock, 1984; Clark, 1993). Despite the importance of wound contraction for wound