Wound repair at a glance

Abstract

This article is part of a Minifocus on collective cell migration. For further reading, please see related articles: `Mechanisms of collective cell migration at a glance' by Olga Ilina and Peter Friedl (J. Cell Sci.122, 3203-3208) and `Collective cell migration in development' by Cornelis Weijer (J. Cell Sci.122, 3215-3223).Wound repair is an essential physiological process that is important for tissue homeostasis, but it can be impaired in disease and contributes to numerous pathologies. The wound healing process, particularly in skin, has been well characterised histologically in studies extending back more than 100 years. Skin is a complex tissue (reviewed by Kanitakis, 2002), and thus a `full-thickness' wound results in damage to many structures, cell layers and lineages, including (from the outside in): the epidermal keratinocyte layer (the body's barrier to the outside world), together with associated epidermal appendages such as hair follicles and sweat glands; the basement membrane (BM) that underlies the epidermis; and the dermis, which is an intricate structure that consists of fibroblasts, extracellular matrix (ECM), nerves, and blood and lymphatic vessels. A wound also causes damage at the level of individual cells (McNeil and Kirchhausen, 2005).A considerable number of different cell lineages play key roles during the various overlapping phases of the repair process (the immediate response; the inflammatory response; the proliferation, migration and contraction phase; and the resolution phase). Here, we summarise the various cell behaviours and their contributions at the wound site. Significant headway has recently been made in our understanding of the genetic basis of wound healing, partly because of the vast amounts of information that have been obtained from microarray studies in which components of the process have been dissected. This article will refer you to these `gene signatures', and also to more focused reviews about the roles of individual cell types in the overall wound-healing process.The immediate response to skin wounding (see poster, panel 1) is a consequence of a barrage of damage signals, which can be both mechanical and chemical. Cells at the edge of a wound are ruptured, as are vessels in the wound vicinity. Damaged and stressed cells respond by activating several `stress signal' pathways within minutes. For example, signaling via the SAPK/JNK and p38 pathways (Kobayashi et al., 2003; Yano et al., 2004) results in phosphorylation of a cascade of signaling molecules, which ultimately culminates in cellular changes including alterations in gene expression, cell survival and metabolism. The same cells leak endogenous molecules, including damage-associated molecular pattern molecules (DAMPs), which might act as activation cues and/or chemotactic factors for other cells in the area (Bianchi, 2007).One of the earliest responses to injury stems from the damage that is caused to local blood vessels. It is necessary to stop local hemorrhage immediately, and this is achieved by platelet activation and aggregation, which results in formation of a fibrin clot consisting of a network of insoluble fibrin fibers. As well as plugging vessels, the clot acts as a provisional matrix to which growth factors bind and through which cells can crawl (Nurden et al., 2008). Activated platelets are themselves an important source of growth factors [such as platelet-derived growth factor, CXCL4, basic fibroblast growth factor, transforming growth factor-β (TGFβ), vascular endothelial growth factor and RANTES (Bahou and Gnatenko, 2004)] and are known to promote various aspects of the repair process through this growth factor release, including angiogenesis, inflammation, and migration of both keratinocytes and fibroblasts.In addition to the platelet-derived growth factors, cells are bathed in other serum factors. Serum, the fluid component of clotted blood, contains many interleukins, colony-stimulating factors, tumour necrosis factor-α, interferon-γ and other components that together lead to induction of serum response factor (SRF). SRF binds to and induces transcription of immediate early and other genes [such as fos, jun and early growth response genes (egr-1 and egr-2) (Chai and Tarnawski, 2002; Grose et al., 2002)]. Transcriptional profiling of in vivo wounds (Cole et al., 2001; Cooper et al., 2005; Deonarine et al., 2007; Roy et al., 2008), and of fibroblasts exposed to serum in vitro (Iyer et al., 1999), reveals an immediate response to wounding in which upwards of several hundred genes are up- or downregulated within an hour of damage.Several other cues that might influence wound cells in vivo include mechanical signals such as `stretch', which occurs in response to changing tissue tensions (Kippenberger et al., 2000); electrical currents that result from membrane damage and breaks in the epithelial barrier (Nuccitelli et al., 2008); and exposure to various microorganisms whose epitopes are large