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Extracellular matrix and wound healing Matrice extracellulaire et cicatrisation F.X. Maquart a,*,b, J.C. Monboisse a,b a b
Laboratoire de biochimie et biologie mole´culaire, CNRS FRE 3481, faculte´ de me´decine, 51, rue Cognacq-Jay, CS 30018, 51095 Reims, France Laboratoire central de biochimie, CHU de Reims, rue Serge-Kochman, 51092 Reims, France
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 December 2013 Accepted 17 February 2014 Available online xxx
Extracellular matrix has been known for a long time as an architectural support for the tissues. Many recent data, however, have shown that extracellular matrix macromolecules (collagens, elastin, glycosaminoglycans, proteoglycans and connective tissue glycoproteins) are able to regulate many important cell functions, such as proliferation, migration, protein synthesis or degradation, apoptosis, etc., making them able to play an important role in the wound repair process. Not only the intact macromolecules but some of their specific domains, that we called ‘‘Matrikines’’, are also able to regulate many cell activities. In this article, we will summarize main findings showing the effects of extracellular matrix macromolecules and matrikines on connective tissue and epithelial cells, particularly in skin, and their potential implication in the wound healing process. These examples show that extracellular matrix macromolecules or some of their specific domains may play a major role in wound healing. Better knowledge of these interactions may suggest new therapeutic targets in wound healing defects. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Extracellular matrix Wound healing Collagen Elastin Glycosaminoglycans Proteoglycans Connective tissue glycoproteins Matrikines
R E´ S U M E´
Mots cle´s : Matrice extracellulaire Cicatrisation Collage`ne E´lastine Glycosaminoglycannes Prote´oglycannes Glycoprote´ines du tissu conjonctif Matrikines
La matrice extracellulaire est connue de longue date comme support architectural pour les tissus. De nombreux re´sultats re´cents indiquent, cependant, que les macromole´cules matricielles (collage`ne, e´lastine, glycosaminoglycannes, prote´oglycannes et glycoprote´ines du tissu conjonctif) sont capables de re´guler de nombreuses fonctions cellulaires telles que la prolife´ration, la migration, la synthe`se ou la de´gradation des prote´ines, l’apoptose, etc., les rendant capables de jouer un roˆle important dans le processus de cicatrisation. Non seulement les mole´cules intactes, mais aussi certains de leurs domaines spe´cifiques, que nous avons appele´s « Matrikines », sont capables de re´guler de nombreuses activite´s cellulaires. Dans cet article, nous re´sumerons les principales de´couvertes montrant les effets des macromole´cules matricielles et des matrikines sur les cellules des tissus conjonctifs et les cellules e´pithe´liales, en particulier dans la peau, et leur implication potentielle dans le processus de cicatrisation. Ces exemples montrent que les macromole´cules de la matrice extracellulaire ou certains de leurs domaines spe´cifiques peuvent jouer un roˆle majeur dans la cicatrisation. Une meilleure connaissance de ces interactions peut sugge´rer de nouvelles cibles the´rapeutiques dans les de´ficits de cicatrisation. ß 2014 Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction Wound healing is a very complex process, associating cellular, molecular, biochemical and physiological events, which permit living organisms to repair accidental lesions. It necessitates the
* Corresponding author. E-mail address: [email protected] (F.X. Maquart).
coordinated intervention of many partners, among which blood cells, epithelial and connective tissue cells, inflammatory cells and many soluble factors, mainly coagulation factors, growth factors and cytokines. It is a dynamic and strongly regulated process implicating molecular, cellular and humoral components, which starts immediately after the initial lesion and will last until complete closure of the wound and restitution of a tissue as functional as possible. In the case of fetal wound, complete
http://dx.doi.org/10.1016/j.patbio.2014.02.007 0369-8114/ß 2014 Elsevier Masson SAS. All rights reserved.
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regeneration of the initial tissue may occur whereas in adults, the wound healing process conducts in most case to the formation of a collagenic scar [1]. Among the factors implicated in the control of the wound healing process, an important partner is the extracellular matrix. It is now well admitted that extracellular matrix is not only an architectural support for the tissues but also plays a major role in cell regulation. Presently, many data show that nearly all the extracellular matrix components are able to regulate cell behaviour. It is clear that the important extracellular matrix alterations that occur during wound healing make it a very important player in this process. This review will summarize main findings showing the effects of extracellular matrix macromolecules on the cells implicated in the wound healing process. A better understanding of the mechanisms involved in these cell-extracellular matrix interactions may suggest new targets for therapeutic strategies in the management of the wound healing defects. 2. The fibrin clot: a provisional matrix As pointed out by Richard Clark many years ago, the fibrin clot by itself constitutes a provisional extracellular matrix, composed of 95% fibrin and many other components, mainly fibronectin, SPARC/osteonectin, thrombospondin and vitronectin. These components may support cell migration necessary for wound healing, but also trigger the inflammation process. For instance, fibrin itself induces the secretion of IL-8 by endothelial cells and of TNFa, IL1ß, IL-6, MIP-1, MIP-2 and MCP-1 by mononuclear cells [2]. Fibrin is rapidly degraded by plasmin and neutrophil elastase. This degradation may induce the release of plasma growth factors trapped in the fibrin lattice, which might play an important role in the early events of wound healing. Fibrin also releases fibrin degradation products, most of which may stimulate the healing process. Fibrin degradation products can induce or amplify the inflammatory process. For instance, fibrinopeptides A and B are chemo-attractant for neutrophils, monocytes and macrophages; D-dimers induce secretion of IL-1ß and IL-6 by mononuclear cells; fragment E induces secretion of IL-1ß and IL-6 by mononuclear cells; fragment ß15-42 is chemo-attractant for neutrophils and fibroblasts (for review, see ref [3]). Fibrin degradation products were also shown to stimulate extracellular matrix deposition [4], fibroblast proliferation [5] and angiogenesis [6]. 3. Extracellular matrix macromolecules as modulators of cell functions in wound healing Extracellular matrix (ECM) is made of collagen and elastic fibers dispersed in a ground substance made of glycosaminoglycans, proteoglycans and connective tissue glycoproteins. Many data have shown that ECM is able to modulate wound repair, either directly by modulating important aspects of cell behaviour such as adhesion, migration, proliferation or survival, or indirectly by modulating extracellular protease secretion, activation and activity, or modulating growth factor activity or bioavailability. Actually, sequestration/release of growth factors by the ECM may prolongate growth factor action or modulate their activity on the cells implicated in the wound healing process. 3.1. Glycosaminoglycans Glycosaminoglycan chains are very important players in wound healing. The most important is hyaluronic acid, a non-sulfated glycosaminoglycan, very abundant in skin [7] where it forms long filaments (500 nm–10 mm) and provides to the tissue its visco-
elasticity and hydrophilicity. Hyaluronic acid, also called hyaluronan, interacts with cell surface receptors, mainly CD-44 and RHAMM (Receptor for HyaluronAn Mediated Mobility), but also Toll-like Receptors TLR-4 and TLR-2, and Inter Cellular Adhesion Molecule-1 (ICAM-1). The interaction of hyaluronan with its receptor induces very important events in the wound repair process: modulation of inflammation, chemotaxis, cell migration, collagen secretion and angiogenesis [8–10]. The abundance of hyaluronan in fetal skin is likely one of the factors which permits to the early gestation fetal skin wound to heal without scar formation [11]. Similarly, the over-expression of hyaluronan synthase-1 is able to induce regenerative wound repair in C57Bl/6 mice [12]. Many data demonstrated that the biological effects of hyaluronan are dependent of its molecular size. For instance, recent data from Ghazi et al. [13] showed that hyaluronan with a molecular weight comprised between 100–300 kDa was able to strongly stimulate keratinocyte migration whereas high molecular weight (1000– 1400 kDa) and low molecular weight (5–20 kDa) hyaluronan fragments had no effect. Earlier, David Raoudi et al. [14] demonstrated that native hyaluronan of high molecular weight (1.7 MDa) stimulated type III collagen production whereas low molecular weight hyaluronan fragments (12 disaccharide units) stimulated type I collagen production by human dermal fibroblasts. Low molecular weight fragments of hyaluronan (10 saccharide units) were also shown to stimulate angiogenesis in rat experimental wounds [15]. Sulfated glycosaminoglycans (chondroitin-sulfate, dermatansulfate, keratan-sulfate and heparan-sulfate) are linked to core proteins to form proteoglycans in normal tissues, especially in skin. Proteoglycan degradation by proteases in the wounds may, however, lead to the release of free glycosaminoglycan chains, which may modulate the wound healing process [16]. For instance, chondroitin-sulfate and dermatan-sulfate regulate growth factor activity and may stimulate nitric oxide production which, in turn, can modulate angiogenesis. Heparan-sulfate stimulates the release of IL-1, IL-6, PGE2 and TGF-ß, inhibits elastase and cathepsin-G activity, complexes chemokines, cytokines and growth factors. It is also well known to stabilize tetrameric complexes between FGF2 or other heparin-binding growth factors and their receptors, improving signal transduction [17]. Heparan sulfate chains may also bind VEGF and contribute to the modulation of its proangiogenic effects in the tissues [18]. 3.2. Proteoglycans Many proteoglycans are involved in the wound healing process. Main skin proteoglycans are small leucine-rich proteoglycans (SLRPs) family and versican, essentially present in the dermis, perlecan in the basement membrane, syndecans and glypicans on the cell surface. Decorin, the first known member of the SLRP family, was shown many years ago to negatively regulate TGF-ß [19]. Delayed wound healing was observed in perlecan-deficient mice, due to an impaired angiogenesis [20]. The V3 isoform of versican was shown to stimulate elastin production [21], to promote angiogenesis [22], and to induce transition of normal dermal fibroblasts to myofibroblasts [23]. Syndecans 1 and 4 are strongly expressed in wounds [24]. Their increased expression stimulate keratinocyte and endothelial cell migration whereas invalidation of the syndecan-4 chain delays wound closure and angiogenesis in mice [25,26]. Threedimensional migration of fibroblasts into fibrin is also decreased when syndecan-4 core protein synthesis is suppressed by anti-sense oligodeoxynucleotides [27]. 3.3. Connective tissue glycoproteins Connective tissue glycoproteins are a group of extracellular matrix macromolecules strongly involved in cell regulation and
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many of them may be involved in the wound healing process, either directly or indirectly. Thrombospondin-1, for instance, is well known for activating latent TGF-ß which [28] in turn, may activate fibroblasts to produce extracellular matrix. Tenascin-C, a matricellular protein transiently expressed during wound healing, was shown to stimulate macrophage and fibroblast activation [29]. It is also a potent stimulator of angiogenesis [30] and is able to protect multipotential mesenchymal stem cells from death cytokines [31]. Fibronectin also plays a crucial role in wound healing by promoting keratinocyte and fibroblast migration, wound contraction, and stabilization of the newly synthetized collagen matrix [32].
[49]. Elastokines interact with their target cells through a specific receptor complex composed of a spliced variant of ß-galactosidase (S-Gal) associated at the cell plasma membrane with neuraminidase-1 (Neu-1) and to cathepsin-A (Cath-A) [50], which binds the consensus sequence GXXPG, a peptide sequence with a type VIII ßturn conformation frequently found in elastin [51]. Laminin 3.3.2 (laminin-5) isoform present in the dermoepidermal junction also contains some domains, especially the LG3 domain of the a3 chain, which stimulate keratinocyte migration and proliferation [52,53]. The many EGF-like domains contained in the tenascin-C amino-acid sequence may also be released by proteases and interact with EGF receptor to stimulate fibroblast proliferation and migration [54].
4. Matrikines in wound healing
5. Small collagen-derived peptides and hypoxia in wound healing
Matrikines are specific domains of extracellular matrix macromolecules, released by partial proteolysis, which are able to modulate many cell activities [33]. Many published data indicate that they may play a major role in the control of wound repair. Matrikines may be produced during proteolytic degradation of extracellular matrix, a process necessary for wound healing. For instance, it was demonstrated that wound healing is severely affected in collagenase-deficient and in plasminogen/plasmindeficient mice [34,35]. The capacity of extracellular matrix macromolecules to exert biological activities on connective tissue cells was demonstrated that a fragment of connective tissue glycoproteins extracted from rabbit dermis was able to inhibit fibroblast proliferation [36]. On the other hand, Laskin et al. [37] demonstrated that collagenderived peptides containing 3 or 5 repeats of the Pro-Hyp-Gly tripeptide were able to exert chemotactic effects on polymorphonuclear neutrophils. One of the best characterized matrikines involved in wound repair is the tripeptide glycyl-histidyl-lysine (GHK) present in many extracellular matrix proteins such as the collagen a2(I), a2(V) and a2(IX) chains, the SPARC glycoprotein, thrombospondin-1, and fibrin a-chain [38]. The peptide may be released from the extracellular matrix proteins by proteases to exert biological effects. It is present in biological fluids under the form of a free or complexed with Cu2+ ions tripeptide [39]. Many data from our laboratory and others demonstrated that GHK has many biological effects in wound healing, such as stimulation of collagen, glycosaminoglycan and proteoglycan synthesis [40] and acceleration of wound healing in vivo [41]. Interestingly, recent data by Choi et al. [42] showed a stem cell recovering effect of copper-free GHK in skin, suggesting a modulating effect of this peptide on stem cell renewal. GHK and GHK-Cu complexes are now found in a lot of cosmetic products for skin repair. They are not, however, the only collagen-derived matrikine since two others, KTTKS (lysylthreonyl-threonyl-lysyl-serine), a penta-peptide derived from the carboxyl-terminal propeptide of type I collagen [43], and GEKG (glycyl-glutamyl-lysyl-glycine), a tetrapeptide derived from the type I collagen triple helical domain [44], were shown to stimulate extracellular matrix macromolecule production. Part of these effects are mediated by an up-regulation of TGFß [45]. Elastin degradation is also an important source of matrikines in pathological tissues. A biological activity of elastin-derived peptides, also called ‘‘elastokines’’ [46], was first demonstrated for kappa-elastin, a mixture of elastin fragments obtained by alkaline hydrolysis of elastic fibers [47], which was shown to modulate ion fluxes in mononuclear cells [48]. Elastokines are able to stimulate many events in the wound healing process: monocytes and polymorphonuclear neutrophil activation, leukocyte migration, chemotaxis, keratinocyte migration, fibroblast proliferation, vasodilatation, angiogenesis, and matrix remodeling
Matrikines are not the only peptides derived from extracellular matrix degradation. Actually, a large amount of proline and hydroxyproline-containing peptides are also released. Among them, Gly-Pro and Gly-Hyp dipeptides stimulate activity of prolidase (EC3.4.13.9), an enzyme which specifically releases proline and hydroxyproline from iminodipeptides [55]. Previous studies of Surazynski et al. [56] demonstrated that overexpression of prolidase resulted in increased hypoxia inducible factor-1a (HIF-1a). This effect was due both to an activation of the hypoxia response element (HRE) by prolidase, resulting in an increased transcription of the HIF-1a gene, and to an inhibition of HIF-1a degradation. Increased levels and increased stability of HIF-1a are responsible for VEGF gene activation which, in turn, activates angiogenesis and improves wound healing [57,58]. 6. The role of integrins in wound healing Integrins are very important partners in wound healing. They mediate attachment of cells to the extracellular matrix. They are also involved in the regulation of cell behaviour and play a major role in cell-extracellular matrix interactions [59]. In the case of wound healing, it was shown that b1-integrin is necessary for keratinocyte migration in vivo and in experimental wounds [60]. Similarly, it was demonstrated that the a3 subunit of a3b1 integrin was able to regulate reepithelialisation during wound healing through SMAD-7 activation [61]. Integrins are also involved in neo-angiogenesis, a very important process in wound healing. Blocking a1 and a2 integrins by specific antibodies suppressed the stimulation of neo-capillary formation by VEGF in dermal microvascular endothelial cells [62]. Similarly, blocking avb3 integrin expression in wound granulation tissue suppressed neo-angiogenesis induced by FGF-2 and TNF-a [63]. 7. Conclusion Intact or partially degraded extracellular matrix macromolecules may play a major role on the activity of the cells implicated in the wound healing process. They may act either directly by interacting with specific receptors of the cell surface membrane such as integrins, CD-44, the elastin receptor complex or others, or indirectly by modulating the activity, activation or bio-availability of many cytokines and growth factors. Every cell type involved in wound healing, inflammatory cells, keratinocytes, fibroblasts, endothelial cells or pluripotent stem cells are concerned by these interactions with extracellular matrix macromolecules or their fragments. Such interactions may constitute new target for the wound healing defects.
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Extracellular matrix and wound healing Matrice extracellulaire et cicatrisation F.X. Maquart a,*,b, J.C. Monboisse a,b a b
Laboratoire de biochimie et biologie mole´culaire, CNRS FRE 3481, faculte´ de me´decine, 51, rue Cognacq-Jay, CS 30018, 51095 Reims, France Laboratoire central de biochimie, CHU de Reims, rue Serge-Kochman, 51092 Reims, France
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 December 2013 Accepted 17 February 2014 Available online xxx
Extracellular matrix has been known for a long time as an architectural support for the tissues. Many recent data, however, have shown that extracellular matrix macromolecules (collagens, elastin, glycosaminoglycans, proteoglycans and connective tissue glycoproteins) are able to regulate many important cell functions, such as proliferation, migration, protein synthesis or degradation, apoptosis, etc., making them able to play an important role in the wound repair process. Not only the intact macromolecules but some of their specific domains, that we called ‘‘Matrikines’’, are also able to regulate many cell activities. In this article, we will summarize main findings showing the effects of extracellular matrix macromolecules and matrikines on connective tissue and epithelial cells, particularly in skin, and their potential implication in the wound healing process. These examples show that extracellular matrix macromolecules or some of their specific domains may play a major role in wound healing. Better knowledge of these interactions may suggest new therapeutic targets in wound healing defects. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Extracellular matrix Wound healing Collagen Elastin Glycosaminoglycans Proteoglycans Connective tissue glycoproteins Matrikines
R E´ S U M E´
Mots cle´s : Matrice extracellulaire Cicatrisation Collage`ne E´lastine Glycosaminoglycannes Prote´oglycannes Glycoprote´ines du tissu conjonctif Matrikines
La matrice extracellulaire est connue de longue date comme support architectural pour les tissus. De nombreux re´sultats re´cents indiquent, cependant, que les macromole´cules matricielles (collage`ne, e´lastine, glycosaminoglycannes, prote´oglycannes et glycoprote´ines du tissu conjonctif) sont capables de re´guler de nombreuses fonctions cellulaires telles que la prolife´ration, la migration, la synthe`se ou la de´gradation des prote´ines, l’apoptose, etc., les rendant capables de jouer un roˆle important dans le processus de cicatrisation. Non seulement les mole´cules intactes, mais aussi certains de leurs domaines spe´cifiques, que nous avons appele´s « Matrikines », sont capables de re´guler de nombreuses activite´s cellulaires. Dans cet article, nous re´sumerons les principales de´couvertes montrant les effets des macromole´cules matricielles et des matrikines sur les cellules des tissus conjonctifs et les cellules e´pithe´liales, en particulier dans la peau, et leur implication potentielle dans le processus de cicatrisation. Ces exemples montrent que les macromole´cules de la matrice extracellulaire ou certains de leurs domaines spe´cifiques peuvent jouer un roˆle majeur dans la cicatrisation. Une meilleure connaissance de ces interactions peut sugge´rer de nouvelles cibles the´rapeutiques dans les de´ficits de cicatrisation. ß 2014 Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction Wound healing is a very complex process, associating cellular, molecular, biochemical and physiological events, which permit living organisms to repair accidental lesions. It necessitates the
* Corresponding author. E-mail address: [email protected] (F.X. Maquart).
coordinated intervention of many partners, among which blood cells, epithelial and connective tissue cells, inflammatory cells and many soluble factors, mainly coagulation factors, growth factors and cytokines. It is a dynamic and strongly regulated process implicating molecular, cellular and humoral components, which starts immediately after the initial lesion and will last until complete closure of the wound and restitution of a tissue as functional as possible. In the case of fetal wound, complete
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regeneration of the initial tissue may occur whereas in adults, the wound healing process conducts in most case to the formation of a collagenic scar [1]. Among the factors implicated in the control of the wound healing process, an important partner is the extracellular matrix. It is now well admitted that extracellular matrix is not only an architectural support for the tissues but also plays a major role in cell regulation. Presently, many data show that nearly all the extracellular matrix components are able to regulate cell behaviour. It is clear that the important extracellular matrix alterations that occur during wound healing make it a very important player in this process. This review will summarize main findings showing the effects of extracellular matrix macromolecules on the cells implicated in the wound healing process. A better understanding of the mechanisms involved in these cell-extracellular matrix interactions may suggest new targets for therapeutic strategies in the management of the wound healing defects. 2. The fibrin clot: a provisional matrix As pointed out by Richard Clark many years ago, the fibrin clot by itself constitutes a provisional extracellular matrix, composed of 95% fibrin and many other components, mainly fibronectin, SPARC/osteonectin, thrombospondin and vitronectin. These components may support cell migration necessary for wound healing, but also trigger the inflammation process. For instance, fibrin itself induces the secretion of IL-8 by endothelial cells and of TNFa, IL1ß, IL-6, MIP-1, MIP-2 and MCP-1 by mononuclear cells [2]. Fibrin is rapidly degraded by plasmin and neutrophil elastase. This degradation may induce the release of plasma growth factors trapped in the fibrin lattice, which might play an important role in the early events of wound healing. Fibrin also releases fibrin degradation products, most of which may stimulate the healing process. Fibrin degradation products can induce or amplify the inflammatory process. For instance, fibrinopeptides A and B are chemo-attractant for neutrophils, monocytes and macrophages; D-dimers induce secretion of IL-1ß and IL-6 by mononuclear cells; fragment E induces secretion of IL-1ß and IL-6 by mononuclear cells; fragment ß15-42 is chemo-attractant for neutrophils and fibroblasts (for review, see ref [3]). Fibrin degradation products were also shown to stimulate extracellular matrix deposition [4], fibroblast proliferation [5] and angiogenesis [6]. 3. Extracellular matrix macromolecules as modulators of cell functions in wound healing Extracellular matrix (ECM) is made of collagen and elastic fibers dispersed in a ground substance made of glycosaminoglycans, proteoglycans and connective tissue glycoproteins. Many data have shown that ECM is able to modulate wound repair, either directly by modulating important aspects of cell behaviour such as adhesion, migration, proliferation or survival, or indirectly by modulating extracellular protease secretion, activation and activity, or modulating growth factor activity or bioavailability. Actually, sequestration/release of growth factors by the ECM may prolongate growth factor action or modulate their activity on the cells implicated in the wound healing process. 3.1. Glycosaminoglycans Glycosaminoglycan chains are very important players in wound healing. The most important is hyaluronic acid, a non-sulfated glycosaminoglycan, very abundant in skin [7] where it forms long filaments (500 nm–10 mm) and provides to the tissue its visco-
elasticity and hydrophilicity. Hyaluronic acid, also called hyaluronan, interacts with cell surface receptors, mainly CD-44 and RHAMM (Receptor for HyaluronAn Mediated Mobility), but also Toll-like Receptors TLR-4 and TLR-2, and Inter Cellular Adhesion Molecule-1 (ICAM-1). The interaction of hyaluronan with its receptor induces very important events in the wound repair process: modulation of inflammation, chemotaxis, cell migration, collagen secretion and angiogenesis [8–10]. The abundance of hyaluronan in fetal skin is likely one of the factors which permits to the early gestation fetal skin wound to heal without scar formation [11]. Similarly, the over-expression of hyaluronan synthase-1 is able to induce regenerative wound repair in C57Bl/6 mice [12]. Many data demonstrated that the biological effects of hyaluronan are dependent of its molecular size. For instance, recent data from Ghazi et al. [13] showed that hyaluronan with a molecular weight comprised between 100–300 kDa was able to strongly stimulate keratinocyte migration whereas high molecular weight (1000– 1400 kDa) and low molecular weight (5–20 kDa) hyaluronan fragments had no effect. Earlier, David Raoudi et al. [14] demonstrated that native hyaluronan of high molecular weight (1.7 MDa) stimulated type III collagen production whereas low molecular weight hyaluronan fragments (12 disaccharide units) stimulated type I collagen production by human dermal fibroblasts. Low molecular weight fragments of hyaluronan (10 saccharide units) were also shown to stimulate angiogenesis in rat experimental wounds [15]. Sulfated glycosaminoglycans (chondroitin-sulfate, dermatansulfate, keratan-sulfate and heparan-sulfate) are linked to core proteins to form proteoglycans in normal tissues, especially in skin. Proteoglycan degradation by proteases in the wounds may, however, lead to the release of free glycosaminoglycan chains, which may modulate the wound healing process [16]. For instance, chondroitin-sulfate and dermatan-sulfate regulate growth factor activity and may stimulate nitric oxide production which, in turn, can modulate angiogenesis. Heparan-sulfate stimulates the release of IL-1, IL-6, PGE2 and TGF-ß, inhibits elastase and cathepsin-G activity, complexes chemokines, cytokines and growth factors. It is also well known to stabilize tetrameric complexes between FGF2 or other heparin-binding growth factors and their receptors, improving signal transduction [17]. Heparan sulfate chains may also bind VEGF and contribute to the modulation of its proangiogenic effects in the tissues [18]. 3.2. Proteoglycans Many proteoglycans are involved in the wound healing process. Main skin proteoglycans are small leucine-rich proteoglycans (SLRPs) family and versican, essentially present in the dermis, perlecan in the basement membrane, syndecans and glypicans on the cell surface. Decorin, the first known member of the SLRP family, was shown many years ago to negatively regulate TGF-ß [19]. Delayed wound healing was observed in perlecan-deficient mice, due to an impaired angiogenesis [20]. The V3 isoform of versican was shown to stimulate elastin production [21], to promote angiogenesis [22], and to induce transition of normal dermal fibroblasts to myofibroblasts [23]. Syndecans 1 and 4 are strongly expressed in wounds [24]. Their increased expression stimulate keratinocyte and endothelial cell migration whereas invalidation of the syndecan-4 chain delays wound closure and angiogenesis in mice [25,26]. Threedimensional migration of fibroblasts into fibrin is also decreased when syndecan-4 core protein synthesis is suppressed by anti-sense oligodeoxynucleotides [27]. 3.3. Connective tissue glycoproteins Connective tissue glycoproteins are a group of extracellular matrix macromolecules strongly involved in cell regulation and
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many of them may be involved in the wound healing process, either directly or indirectly. Thrombospondin-1, for instance, is well known for activating latent TGF-ß which [28] in turn, may activate fibroblasts to produce extracellular matrix. Tenascin-C, a matricellular protein transiently expressed during wound healing, was shown to stimulate macrophage and fibroblast activation [29]. It is also a potent stimulator of angiogenesis [30] and is able to protect multipotential mesenchymal stem cells from death cytokines [31]. Fibronectin also plays a crucial role in wound healing by promoting keratinocyte and fibroblast migration, wound contraction, and stabilization of the newly synthetized collagen matrix [32].
[49]. Elastokines interact with their target cells through a specific receptor complex composed of a spliced variant of ß-galactosidase (S-Gal) associated at the cell plasma membrane with neuraminidase-1 (Neu-1) and to cathepsin-A (Cath-A) [50], which binds the consensus sequence GXXPG, a peptide sequence with a type VIII ßturn conformation frequently found in elastin [51]. Laminin 3.3.2 (laminin-5) isoform present in the dermoepidermal junction also contains some domains, especially the LG3 domain of the a3 chain, which stimulate keratinocyte migration and proliferation [52,53]. The many EGF-like domains contained in the tenascin-C amino-acid sequence may also be released by proteases and interact with EGF receptor to stimulate fibroblast proliferation and migration [54].
4. Matrikines in wound healing
5. Small collagen-derived peptides and hypoxia in wound healing
Matrikines are specific domains of extracellular matrix macromolecules, released by partial proteolysis, which are able to modulate many cell activities [33]. Many published data indicate that they may play a major role in the control of wound repair. Matrikines may be produced during proteolytic degradation of extracellular matrix, a process necessary for wound healing. For instance, it was demonstrated that wound healing is severely affected in collagenase-deficient and in plasminogen/plasmindeficient mice [34,35]. The capacity of extracellular matrix macromolecules to exert biological activities on connective tissue cells was demonstrated that a fragment of connective tissue glycoproteins extracted from rabbit dermis was able to inhibit fibroblast proliferation [36]. On the other hand, Laskin et al. [37] demonstrated that collagenderived peptides containing 3 or 5 repeats of the Pro-Hyp-Gly tripeptide were able to exert chemotactic effects on polymorphonuclear neutrophils. One of the best characterized matrikines involved in wound repair is the tripeptide glycyl-histidyl-lysine (GHK) present in many extracellular matrix proteins such as the collagen a2(I), a2(V) and a2(IX) chains, the SPARC glycoprotein, thrombospondin-1, and fibrin a-chain [38]. The peptide may be released from the extracellular matrix proteins by proteases to exert biological effects. It is present in biological fluids under the form of a free or complexed with Cu2+ ions tripeptide [39]. Many data from our laboratory and others demonstrated that GHK has many biological effects in wound healing, such as stimulation of collagen, glycosaminoglycan and proteoglycan synthesis [40] and acceleration of wound healing in vivo [41]. Interestingly, recent data by Choi et al. [42] showed a stem cell recovering effect of copper-free GHK in skin, suggesting a modulating effect of this peptide on stem cell renewal. GHK and GHK-Cu complexes are now found in a lot of cosmetic products for skin repair. They are not, however, the only collagen-derived matrikine since two others, KTTKS (lysylthreonyl-threonyl-lysyl-serine), a penta-peptide derived from the carboxyl-terminal propeptide of type I collagen [43], and GEKG (glycyl-glutamyl-lysyl-glycine), a tetrapeptide derived from the type I collagen triple helical domain [44], were shown to stimulate extracellular matrix macromolecule production. Part of these effects are mediated by an up-regulation of TGFß [45]. Elastin degradation is also an important source of matrikines in pathological tissues. A biological activity of elastin-derived peptides, also called ‘‘elastokines’’ [46], was first demonstrated for kappa-elastin, a mixture of elastin fragments obtained by alkaline hydrolysis of elastic fibers [47], which was shown to modulate ion fluxes in mononuclear cells [48]. Elastokines are able to stimulate many events in the wound healing process: monocytes and polymorphonuclear neutrophil activation, leukocyte migration, chemotaxis, keratinocyte migration, fibroblast proliferation, vasodilatation, angiogenesis, and matrix remodeling
Matrikines are not the only peptides derived from extracellular matrix degradation. Actually, a large amount of proline and hydroxyproline-containing peptides are also released. Among them, Gly-Pro and Gly-Hyp dipeptides stimulate activity of prolidase (EC3.4.13.9), an enzyme which specifically releases proline and hydroxyproline from iminodipeptides [55]. Previous studies of Surazynski et al. [56] demonstrated that overexpression of prolidase resulted in increased hypoxia inducible factor-1a (HIF-1a). This effect was due both to an activation of the hypoxia response element (HRE) by prolidase, resulting in an increased transcription of the HIF-1a gene, and to an inhibition of HIF-1a degradation. Increased levels and increased stability of HIF-1a are responsible for VEGF gene activation which, in turn, activates angiogenesis and improves wound healing [57,58]. 6. The role of integrins in wound healing Integrins are very important partners in wound healing. They mediate attachment of cells to the extracellular matrix. They are also involved in the regulation of cell behaviour and play a major role in cell-extracellular matrix interactions [59]. In the case of wound healing, it was shown that b1-integrin is necessary for keratinocyte migration in vivo and in experimental wounds [60]. Similarly, it was demonstrated that the a3 subunit of a3b1 integrin was able to regulate reepithelialisation during wound healing through SMAD-7 activation [61]. Integrins are also involved in neo-angiogenesis, a very important process in wound healing. Blocking a1 and a2 integrins by specific antibodies suppressed the stimulation of neo-capillary formation by VEGF in dermal microvascular endothelial cells [62]. Similarly, blocking avb3 integrin expression in wound granulation tissue suppressed neo-angiogenesis induced by FGF-2 and TNF-a [63]. 7. Conclusion Intact or partially degraded extracellular matrix macromolecules may play a major role on the activity of the cells implicated in the wound healing process. They may act either directly by interacting with specific receptors of the cell surface membrane such as integrins, CD-44, the elastin receptor complex or others, or indirectly by modulating the activity, activation or bio-availability of many cytokines and growth factors. Every cell type involved in wound healing, inflammatory cells, keratinocytes, fibroblasts, endothelial cells or pluripotent stem cells are concerned by these interactions with extracellular matrix macromolecules or their fragments. Such interactions may constitute new target for the wound healing defects.
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