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Manon C Zweers

Publications and source records attributed to Manon C Zweers.

8 recordsLinked to original sources
PubMed2006

Integrin alpha2beta1 is required for regulation of murine wound angiogenesis but is dispensable for reepithelialization.

The alpha2beta1 integrin functions as the major receptor for collagen type I on a large number of different cell types, including keratinocytes, fibroblasts, endothelial cells, and a variety of inflammatory cells. Recently, we demonstrated that adhesion of keratinocytes to collagen critically depends on alpha2beta1, whereas fibroblasts can partly compensate for loss of alpha2beta1 in simple adhesion to collagen. However, in three-dimensional collagen matrices, alpha2beta1-null fibroblasts are hampered in generating mechanical forces. These data suggested a pivotal role for alpha2beta1 during wound healing in vivo. Unexpectedly, reepithelialization of excisional wounds of alpha2beta1-null mice was not impaired, indicating that keratinocytes do not require adhesion to or migration on collagen for wound closure. Whereas wound contraction and myofibroblast differentiation were similar, wound tensile strain was reduced in alpha2beta1-null mice, suggesting subtle changes in organization of the extracellular matrix. In addition, we observed reduced influx of mast cells into the granulation tissue, whereas infiltration of other inflammatory cells was not impaired. Interestingly, ablation of alpha2beta1 resulted in strong enhancement of neovascularization of granulation tissue and sponge implants. Both ultrastructurally and functionally, these new blood vessels appeared intact. In conclusion, our data show unique and overlapping functions of alpha2beta1 integrin during murine cutaneous wound healing.

Animals↗
PubMed2006

Integrin alpha2beta1 deficiency does not affect contact hypersensitivity.

Collagens in the extracellular matrix are thought to play an important role in regulating inflammatory responses by affecting cell adhesion and migration. The contact between collagens and cells is established mainly by alpha1beta1, alpha2beta1 and alpha11beta1integrin receptors. Here, we analyzed the contact hypersensitivity (CHS) reaction in mice that were genetically deficient in the collagen receptor alpha2beta1. Integrin alpha2beta1 is widely expressed and has been suggested to play an important role in mediating inflammatory responses. CHS was induced by applying dinitrofluorobenzene to abdominal skin and challenging with the same reagent on ear skin. Macroscopically and histologically, ear swelling in alpha2beta1-deficient mice did not differ from that in wild-type control mice. Immunohistological detection of infiltrated T lymphocytes, neutrophils and mast cells in inflamed ear skin revealed similar numbers in controls and integrin alpha2beta1-deficient animals. Our results suggest that the adhesive functions of integrin alpha2beta1 are dispensable for the CHS response; they may be compensated for by the collagen receptor alpha1beta1 or other collagen receptors.

Animals↗
PubMed2006

Abdominal aortic aneurysm is associated with high serum levels of tenascin-X and decreased aneurysmal tissue tenascin-X.

BACKGROUND: Tenascin-X is a large extracellular matrix protein that is abundantly expressed in several connective tissues. A 140-kDa C-terminal fragment of tenascin-X is present in human serum. Complete deficiency of tenascin-X is associated with Ehlers-Danlos syndrome, and these patients show major connective tissue alterations in their skin, as well as blood vessel fragility. In this study, we investigated whether tenascin-X is present in normal human aorta and abdominal aortic aneurysm (AAA) tissues and whether an association exists between serum tenascin-X levels and AAA. METHODS AND RESULTS: Five normal aortas and 5 AAA tissues were immunostained for tenascin-X and elastin. Tenascin-X was present throughout the entire aorta and was especially abundant near the elastic lamellae, whereas tenascin-X expression was strongly decreased in AAA tissue. Measurement of tenascin-X serum concentration by enzyme-linked immunosorbent assay (ELISA) in 87 AAA patients and 86 controls demonstrated an increasing risk for AAA with increasing tenascin-X serum concentrations. After adjustment for established risk factors, tenascin-X serum concentrations in the highest quartile were associated with a 5-fold increase in risk of AAA (odds ratio, 5.3; 95% confidence interval, 2.0 to 13.8). CONCLUSIONS: Tenascin-X expression is markedly decreased in AAA tissue, and AAA is associated with high serum concentrations of tenascin-X.

Aged↗
PubMed2006

Mechanical tension and integrin alpha 2 beta 1 regulate fibroblast functions.

The extracellular matrix (ECM) environment in connective tissues provides fibroblasts with a structural scaffold and modulates cell shape, but it also profoundly influences the fibroblast phenotype. Here we studied fibroblasts cultured in a three-dimensional network of native collagen, which was either mechanically stressed or relaxed. Mechanical load induces fibroblasts that synthesize abundant ECM and a characteristic array of cytokines/chemokines. This phenotype is reminiscent of late granulation tissue or scleroderma fibroblasts. By contrast, relaxed fibroblasts are characterized by induction of proteases and a subset of cytokines that does not overlap with that of mechanically stimulated cells. Thus, the biochemical composition and physical nature of the ECM exert powerful control over the phenotypes of fibroblasts, ranging from "synthetic" to "inflammatory" phenotypes. Interactions between fibroblasts and collagen fibrils are mostly mediated by a subset of beta 1 integrin receptors. Fibroblasts utilize alpha 1 beta 1, alpha 2 beta 1, and alpha 11 beta 1 integrins for establishing collagen contacts and transducing signals. In vitro assays and mouse genetics have demonstrated individual tasks served by each receptor, but also functional redundancy. Unraveling the integrated functions of fibroblasts, collagen integrin receptors, collagen fibrils, and mechanical tension will be important to understand the molecular mechanisms underlying tissue repair and fibrosis.

Animals↗
PubMed2004

Transplantation of reconstructed human skin on nude mice: a model system to study expression of human tenascin-X and elastic fiber components.

Tenascin-X is a large extracellular matrix protein that is widely expressed in connective tissues during development and in the adult. Genetically determined deficiency of tenascin-X causes the connective tissue disease Ehlers-Danlos syndrome. These patients show reduced collagen density and fragmentation of elastic fibers in their skin. In vitro studies on the role of tenascin-X in elastic fiber biology are hampered because monolayers of fibroblasts do not deposit tenascin-X and elastic fibers into the extracellular matrix. Here, we applied an organotypic culture model of fibroblasts and keratinocytes to address this issue. We investigated the deposition of tenascin-X and elastin into skin-equivalent in vitro and also in vivo after transplantation onto immunodeficient mice. Whereas tenascin-C and fibrillin-1 were readily expressed in the skin-equivalents before transplantation, tenascin-X and elastin were not present. Three weeks post-grafting, a network of elastin was observed that coincided with the appearance of tenascin-X. At the ultrastructural level, microfibrils were observed, some of which were associated with elastin. Transplanted skin-equivalents containing tenascin-X-deficient fibroblasts showed deposition of immunoreactive elastin in similar quantities and distribution as those containing control fibroblasts. This suggests that tenascin-X is important for the stability and maintenance of established elastin fibers, rather than for the initial phase of elastogenesis. Thus, the transplantation of reconstructed skin on nude mice allows the study of tenascin-X and elastin expression and could be used as a model system to study the potential role of tenascin-X in matrix assembly and stability.

Animals↗
PubMed2004

Deficiency of tenascin-X causes abnormalities in dermal elastic fiber morphology.

Deficiency of the extracellular matrix protein tenascin-X (TNX) was recently described as the molecular basis of a new, recessive type of Ehlers-Danlos syndrome. Here we report gross abnormalities of the elastic fibers and microfibrils in the dermis of these patients, and reduced dermal collagen content, as determined by quantitative image analysis. The ascending, fine elastic fibers in the papillary dermis were absent or inconspicuous and had few branches. The coarse elastic fibers of the reticular dermis were fragmented and clumped. At the ultrastructural level, irregular and immature elastin fibers and fibers devoid of microfibrils were observed. In TNX-deficient patients the dermal collagen density was reduced, but no structural abnormalities in the collagen fibrils were found. These findings suggest that both elastic fiber abnormalities and reduced collagen content contribute to the observed phenotype in TNX-deficient patients.

Adult↗