Injury to the skin initiates a cascade of events including inflammation, new tissue formation, and tissue remodeling, which finally lead to at least partial reconstruction of the wounded area (57, 176; Fig. 1). The repair process is initiated immediately after injury by the release of various growth factors, cytokines, and low-molecular-weight compounds from the serum of injured blood vessels and from degranulating platelets. Disruption of blood vessels also leads to the formation of the blood clot, which is composed of cross-linked fibrin, and of extracellular matrix proteins such as fibronectin, vitronectin, and thrombospondin (56, 57, 176). Apart from providing a barrier against invading microorganisms, the blood clot also serves as a matrix for invading cells and as a reservoir of growth factors required during the later stages of the healing process. Within a few hours after injury, inflammatory cells invade the wound tissue. Neutrophils arrive first within a few minutes, followed by monocytes and lymphocytes. They produce a wide variety of proteinases and reactive oxygen species as a defense against contaminating microorganisms, and they are involved in the phagocytosis of cell debris. In addition to these defense functions, inflammatory cells are also an important source of growth factors and cytokines, which initiate the proliferative phase of wound repair. The latter starts with the migration and proliferation of keratinocytes at the wound edge and is followed by proliferation of dermal fibroblasts in the neighborhood of the wound. These cells subsequently migrate into the provisional matrix and deposit large amounts of extracellular matrix. Furthermore, wound fibroblasts acquire a contractile phenotype and transform into myofibroblasts, a cell type which plays a major role in wound contraction. Massive angiogenesis leads to the formation of new blood vessels, and nerve sprouting occurs at the wound edge. The resulting wound connective tissue is known as granulation tissue because of the granular appearance of the numerous capillaries. Finally, a transition from granulation tissue to mature scar occurs, characterized by continued collagen synthesis and collagen catabolism. The scar tissue is mechanically insufficient and lacks appendages, including hair follicles, sebaceous glands, and sweat glands. Scarring can also be excessive, leading to hypertrophic scars and keloids. In contrast, wound healing in mammalian embryos until the beginning of the third trimester results in essentially perfect repair, suggesting fundamental differences in the healing process between embryonic and adult mammals (57, 168, 176).
In addition to the importance of cell-cell and cell-matrix interactions, all stages of the repair process are controlled by a wide variety of different growth factors and cytokines. Multiple studies have demonstrated a beneficial effect of many of these growth factors, e.g., platelet-derived growth factors (PDGFs), fibroblast growth factors (FGFs), and granulocyte-macrophage colony stimulating factor (GM-CSF) on the healing process, both in animal models and also in patients suffering from different types of wound healing disorders (1, 79, 107, 115, 196). However, the roles of endogenous growth factors in the healing response have been only partially elucidated, and in most cases, the suggested function of these molecules is based on descriptive expression studies and/or functional cell culture data. However, in vivo functions of many growth factors remain largely unconfirmed.
The development of transgenic and knock-out mouse technologies has provided new insights into the function of many different genes during embryonic development. These technologies allow gain of function experiments (overexpression of genes) as well as loss of function experiments (gene knock-outs by homologous recombination in embryonic stem cells or overexpression of dominant-negative mutants). Most importantly, spatial and temporal control of gene ablation or overexpression, using both inducible and cre-lox technologies, makes it possible to determine the functions of proteins formerly precluded due to embryonic lethality. A large number of viable genetically modified mice are now available that can be used to elucidate the role of the deleted, mutated, or overexpressed genes in different types of repair processes. Indeed, the past years have seen an exponential growth in the number of genetically modified mice that were used for wound healing experiments, and these studies have provided interesting, and often unexpected, results concerning the in vivo function of growth factors in wound repair (see http://icbxs.biol.ethz.ch/members/grose/woundtransgenic/home.html). In this review, we summarize the reported expression and function of endogenous growth factors and cytokines in cutaneous wound repair. Results of experiments with exogenous growth factors for the treatment of wound repair are only mentioned briefly, and reviews are cited wherever possible. In addition, we focus on those growth factors and cytokines for which results from functional in vivo studies are available.