Lygoe, Kate Alexandra; (2004) Modulation of the myofibroblast phenotype is via interaction of extracellular matrix proteins with integrin receptors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Myofibroblasts are differentiated fibroblast cells and are implicated in a wide range of normal and pathological conditions. They are characterised by the production of the cytoskeletal protein α-smooth muscle actin (α-sma), contained within stress fibres and the production of abundant amounts of extracellular matrix (ECM) proteins. They play an important role in normal wound contraction and scar production as well as in embryogenesis, fibrosis, hypertrophic scarring and tumourigenesis. Differentiation of fibroblast to myofibroblast can be brought about by stimulation of the cells with the multifunctional cytokine transforming growth factor -β1 (TGF-β1), which has also been implicated in ECM deposition. This suggests a situation where myofibroblast differentiation, TGF-β1, and the ECM are intimately connected. Interaction of myofibroblasts with their surrounding matrix involves cell surface integrin receptors. The aims of the study were: (i) to identify the integrin involvement in fibroblast to myofibroblast differentiation. (ii) to establish whether such participation in the differentiation process had implications in cell contraction, cell migration and MMP-2 production. (iii) to determine any phenotypic differences between oral and dermal fibroblasts and their implication in scarless wound healing (iv) to discover the implication of myofibroblast differentiation in tumour progression by investigating whether oral squamous cell carcinoma cells are able to generate myofibroblasts and the effect that these cells then have on tumour invasion and progression. A panel of integrins on human oral and dermal fibroblasts and myofibroblasts were screened by flow cytometry and Western blotting. Initially 3 integrin subunits (αv, α5 and β1) were targeted for blocking studies. By adding blocking antibodies simultaneously to TGF-β1 it was discovered that the α-sma upregulation seen upon differentiation was prevented. This prevention of differentiation also inhibited the TGF-β1-induced collagen gel contraction. The integrins subunits were also found to play a part in cell migration, but were unrelated to Matrix Metalloproteinase (MMP) -2 production in both fibroblasts and TGF-β1 induced myofibroblasts. Oral squamous cell carcinoma cell lines were able to generate a myofibroblast phenotype in human oral fibroblasts. These myofibroblasts in turn increased the carcinoma cell invasion.

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