Expression of Integrin αvβ6 and TGF-β in Scarless vs Scar-forming Wound Healing (original) (raw)
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The Journal of Cell Biology
The molecular mechanism underlying the promotion of wound healing by TGF-/31 is incompletely understood. We report that TGF-/5'I regulates the regenerative/migratory phenotype of normal human keratinocytes by modulating their integrin receptor repertoire. In growing keratinocyte colonies but not in fully stratified cultured epidermis, TGF-~I: (a) strongly upregulates the expression of the fibronectin receptor c~5~1, the vitronectin receptor t~v/~5, and the collagen receptor t~2/~l by differentially modulating the synthesis of their ot and/~ subunits; (b) downregulates the multifunctional oL3/~l heterodimer; (c) induces the de novo expression and surface exposure of the av#6 fibronectin receptor; (d) stimulates keratinocyte migration toward fibronectin and vitronectin; (e) induces a marked perturbation of the general mecha-nism of polarized domain sorting of both #1 and ~4 dimers; and (f) causes a pericellular redistribution of ~v/~5. These data suggest that ot5~l, ave6, and av/~5, not routinely used by keratinocytes resting on an intact basement membrane, act as "emergency" receptors, and uncover at least one of the molecular mechanisms responsible for the peculiar integrin expression in healing human wounds. Indeed, TGF-~I reproduces the integrin expression pattern of keratinocytes located at the injury site, particularly of cells in the migrating epithelial tongue at the leading edge of the wound. Since these keratinocytes are inhibited in their proliferative capacity, these data might account for the apparent paradox of a TGF-/5'l-dependent stimulation of epidermal wound healing associated with a growth inhibitory effect on epithelial cells. . somes. These structures link the epithelial intermediate filament network to the dermal anchoring fibrils, which are mainly composed of type VII collagen and extend from the basement membrane to anchoring plaques in the papillary dermis . The keratinocyte behavior changes dramatically when a wound occurs and the epidermis undergoes regeneration. Indeed, wound healing is a complex phenomenon that occurs through a sequence of controlled events including: (a) an inflammatory stage involving aggregation of platelets and recruitment of macrophages, fibroblasts, and lymphocytes at the injury stie; (b) the formation of a provisional extracellular matrix, mainly composed of fibrinogen, fibrin, collagens, fibronectin, tenascin, and vitronectin; (c) the recruitment of epidermal stem cells at the injury boundary, as well as the formation of an epithelial tongue of migrating keratinocytes at the very edge of the wound; and (d) the local synthesis and secretion, operated by the cell types mentioned above, of a wide variety of growth factors and cytokines regulating the formation of the granulating tissue, the migration and proliferation of keratinocytes, and the final remodeling of the scar, through a The rabbit polyclonal antiserum to 183 and the goat antiserum to fll have been described . The rabbit polyclonal antiserum to f16 ) was a generous gift from V. Quaranta (Scripps Research Institute, La Jolla, CA); the rabbit polyclonal antiserum to f15, the murine mAb B5-IA9 to/$5, and the mAb TS2/7 to cd were gifts from M. Hemler,
Increased Expression of β6-Integrin in Skin Leads to Spontaneous Development of Chronic Wounds
The American Journal of Pathology, 2004
Integrin ␣v6 is an epithelial cell-specific receptor that is not normally expressed by resting epithelium but its expression is induced during wound healing. The function of ␣v6-integrin in wound repair is not clear. In the present study, we showed that 6-integrin expression was strongly up-regulated in the epidermis in human chronic wounds but not in different forms of skin fibrosis. To test whether increased 6integrin expression plays a role in abnormal wound healing we developed four homozygous transgenic mouse lines that constitutively expressed human 6integrin in the epithelium. The mice developed normally and did not show any histological abnormalities in the skin. The rate of experimental skin wound closure was unaltered and the wounds healed without significant scar formation. However, during breeding program 16.1 to 27.0% of transgenic mice developed spontaneous, progressing fibrotic chronic ulcers. None of the wild-type animals developed these lesions. The chronic lesions had areas with severe fibrosis and numerous activated macrophages and fibroblasts expressing transforming growth factor (TGF)-. The level of TGF-1 was significantly increased in the lesions as compared with normal skin. The findings suggest that increased ␣v6-integrin in keratinocytes plays an active part in abnormal wound healing possibly through a mechanism involving increased activation of TGF-.
Role of integrins in wound repair and its periodontal implications
Journal of oral biology and craniofacial research
Wound healing in human periodontium is a complex process which involves both cell-cell and cell-matrix interactions. Integrins play a major role in regulation of these cell-cell, cell-matrix interaction. Wound healing involves two major events i.e. re-epithelialization and connective tissue repair. In this concise review, we will discuss the role of integrins in these major events as well as their impIications in periodontal wound repair. Integrins are differentially expressed in both of these major events. In re-epithelialization, keratinocytes express novel integrins receptors αvβ1, α5β1and αvβ6 which are not expressed in normal healthy epithelium. Re-epithelialization also involves interaction of integrins with TGF-β and fibronectin. Similarly, in connective tissue repair, the activation of fibroblast as well as the expression of integrins α5β1 and α3β1 is upregulated. In healthy periodontium, integrin αvβ6 is normally expressed in junctional epithelium which is generally express...
Role of Elevated Plasma Transforming Growth Factor-β1 Levels in Wound Healing
The American Journal of Pathology, 1999
Transforming growth factor (TGF)-1 plays a central role in wound healing. Wounds treated with neutralizing antibody to TGF-1 have a lower inflammatory response , reduced early extracellular matrix deposition , and reduced later cutaneous scarring , indicating the importance of local tissue TGF-1. By contrast, increasing the local , tissue levels of TGF-1 increases the early extracellular matrix deposition but does not alter scar formation. Increased levels of plasma TGF-1 correlate with increased fibrogenesis in the lung , kidneys , and liver. The aim of the present study was to investigate the role of elevated systemic levels of TGF-1 on wound healing. We used transgenic mice that express high levels of active TGF-1 and have elevated plasma levels of TGF-1 and wild-type mice of the same strain as controls. Incisional wounds and subcutaneously implanted polyvinyl alcohol (PVA) sponges were analyzed. Surprisingly, cutaneous wounds in transgenic , TGF-1-overexpressing mice healed with reduced scarring accompanied by an increase in the immunostaining for TGF-3 and TGF--receptor RII and a decrease in immunostaining for TGF-1 compared with wounds in control mice. By contrast , the PVA sponges showed the opposite response , with PVA sponges from transgenic mice demonstrating an enhanced rate of cellular influx and matrix deposition into the sponges accompanied by an increase in the immunostaining for all three TGF- isoforms and their receptors compared with PVA sponges from control mice. Together , the data demonstrate that increased circulating levels of TGF-1 do not always result in increased expression or activity in selected target tissues such as the skin. The two wound models , subcutaneously implanted PVA sponges and cutaneous incisional wounds , differ significantly in terms of host response patterns. Finally, the data reinforce our previous observations that the relative ratios of the three TGF- isoforms is critical for control of scarring. M. Shah was supported by a travel grant from the Wellcome Trust.
Journal of Immunology Research
Wound healing is a complex biologic process evolving in three phases: inflammation, proliferation, and tissue remodeling controlled by numerous growth factors and cytokines. Oral mucosa wounds heal with significantly less important scars with less numerous macrophages and mast cells and more numerous myofibroblasts than cutaneous counterparts. We analyzed 32 cutaneous and 32 oral mucosa scars for TGFbeta1, TGFbeta2, TGFbeta3, TNFalpha, PDGF BB and FGF1 expression in mesenchymal cells, endothelial cells, macrophages, and multinucleated giant cells. We identified differences in the expression of profibrotic and antifibrotic factors in oral mucosa and skin scars; TGFbeta2 was positive in cutaneous multinucleated giant cells, TNFalpha was positive in cutaneous macrophages, and both were negative in oral mucosa while TGFbeta3 was positive in oral macrophages and mostly negative in cutaneous ones. PDGF BB and FGF1 were positive in oral endothelial cells and oral macrophages and negative i...
Dynamics of Transforming Growth Factor Beta Signaling in Wound Healing and Scarring
Advances in wound care, 2013
Wound healing is an intricate biological process in which the skin, or any other tissue, repairs itself after injury. Normal wound healing relies on the appropriate levels of cytokines and growth factors to ensure that cellular responses are mediated in a coordinated manner. Among the many growth factors studied in the context of wound healing, transforming growth factor beta (TGF-β) is thought to have the broadest spectrum of effects. Many of the molecular mechanisms underlying the TGF-β/Smad signaling pathway have been elucidated, and the role of TGF-β in wound healing has been well characterized. Targeting the TGF-β signaling pathway using therapeutic agents to improve wound healing and/or reduce scarring has been successful in pre-clinical studies. Although TGF-β isoforms (β1, β2, β3) signal through the same cell surface receptors, they display distinct functions during wound healing in vivo through mechanisms that have not been fully elucidated. The challenge of translating pre...
Synthetic TGF-b antagonist accelerates wound healing and reduces scarring
The FASEB Journal, 2002
Wound healing consists of re-epithelialization, contraction and formation of granulation and scar tissue. TGF-β is involved in these events, but its exact roles are not well understood. Here we demonstrate that topical application of a synthetic TGF-β antagonist accelerates re-epithelialization in pig burn wounds (100% re-epithelialization in antagonist-treated wounds vs. ~ 70% reepithelialization in control wounds on postburn day 26) and reduces wound contraction and scarring in standard pig skin burn, pig skin excision and rabbit skin excision wounds. These results support the distinct roles of TGF-β in the complex process of wound healing and demonstrate the feasibility of manipulating wound healing by TGF-β antagonist.