Illustrations
Figure 1
Re-epithelialization at day 0: keratinocyte activation in response to injury. A) After an injury, keratinocytes adjacent to the wound release pre-stored IL-1. IL-1 acts in an autocrine manner and induces the expression and release of TNFα. In response to these stimuli keratinocytes are activated and alert the surrounding tissues. B) Activation of keratinocytes promotes the production of new cytokines and growth factors. Release of prestored IL-1 by keratinocytes induces the production of cytokines and growth factors (TNFα, GM-CSF, TGFα and IL-1) that act in an autocrine manner to promote morphological changes and expression of new genes like keratins 6 and 16, as well as more growth factors and cytokines. IL-1 and TNFα also activate dermal fibroblasts to produce FGF-7 that stimulates epithelialization and triggers the inflammatory cascade in a paracrine way.
Figure 1
Figure 2
Re-epithelialization from days 1 to 5 post-injury. A) Keratinocyte migration and proliferation. Approximately 24h after injury, activated basal and suprabasal keratinocytes adjacent to the wound edges undergo dramatic morphological changes to acquire a motile phenotype and start migrating to cover the wounded area. Additionally, new set of genes are induced to produce new integrins, syndecan-1, growth factors, cytokines and MMPs that participate in the repeated cycles of cell attachment and retraction, in the degradation of ECM components and in the release and cleavage of bioactive molecules in a-gain-of-function manner. Keratinocytes behind the wound edges start proliferating to enrich the migrating tongue. B) Cross-talk between keratinocytes and other cell types. Other cells such as, fibroblasts, endothelial cells, blood cells and immune cells participate in re-epithelialization by producing growth factors and cytokines with paracrine effects that impinge on keratinocyte gene expression and thus, promote migration and proliferation. All growth factors and cytokines produced are listed.
Figure 2
Figure 3
Domain structure of the matrix metalloproteinase (MMP) family. All human MMPs consist at least of a signal peptide, a pro-domain and a catalytic domain. The pro-domain contains the conserved cysteine motif, which binds to the catalytic Zn2+ in the zymogen. The catalytic domain contains the conserved catalytic sequence. MMP-7 and -26 are the MMPs with the simplest structural organization. The gelatinases MMP-2 and MMP-9 contain three fibronectin repeats within their catalytic domain. Some MMPs have a furin recognition site ahead of the catalytic domain, which allows intracellular activation of the zymogen by furin. All MMPs, except MMP-7 and -26, have a flexible proline-rich hinge region and a haemopexin-like C-terminal domain, which participate in substrate recognition. The membrane MMPs, MMP-14, -15, -16, and -24 contain additionally a transmembrane type I domain, while MMP-23 contains a type II transmembrane domain and an immunoglobulin-like domain. MMP-17 and -25 are integrated in the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor.
Figure 3
Figure 4
MMPs involved in the re-epithelialization process. A) Spatial organization of MMP expression in the epidermis during re-epithelialization. MMP-10 is localized at the tip of the migrating tongue. MMP-1 and MMP-9 are expressed by migrating keratinocytes at the front edge. MMP-3, MMP-19 and MMP-28 are localized behind the front edge at the site of proliferative epithelium. B) Possible modes of MMP action in the re-epithelialization. MMP-7 is associated with the disruption of cell-cell junctions. MMP-3 is likely to participate in the re-epithelialization by activating other MMPs, while MMP-19 is associated with keratinocyte proliferation and the release of IGF. MMP-9 has been localized at the sites of attachment of keratinocytes with the intact basement membrane. MMP-9 is likely to be involved in the re-epithelialization by degrading collagen IV. MMP-10 has been associated with laminin 332 deposition and cleavage, and proper orientation of keratinocyte migration. MMP-1 participates in the repeated cycles of cell adhesion and retraction.
Figure 4
Tableaux
Auteurs
Laboratoire de biologie tissulaire et d’ingénierie thérapeutique,
Institut de Biologie et Chimie des Protéines,
UMR 5305, CNRS; Université Lyon 1,
7 passage du Vercors, 69367, Lyon, France
Skin wound healing is a complex process in which dermal and epidermal events are closely related and is not, as was long believed, a simple linear process in which growth factors are synthesized to activate cell proliferation and migration. Rather, skin repair is the result of several dynamic and interactive processes involving soluble factors, blood elements, extracellular matrix (ECM) components, and cells [1]. In normal conditions, it may be divided into four continuous phases, namely haemostasis, [...]