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Thy-1 Expression Inhibits Myofibroblastic Differentiation of Profibrotically Stimulated Rat Lung Fibroblasts

Abstract

Idiopathic pulmonary fibrosis (IPF) has been characterized by aberrant scarring of the lung tissue as a result of myofibroblastic differentiation of lung fibroblasts and epithelial cells. It has been estimated to affect up to 120,000 individuals in the United States alone, with no effective available treatment. In IPF, myofibroblasts localize within characteristic lesions termed fibroblastic foci, triggering the deposition and excess accumulation of extracellular matrix (ECM) proteins. Previous evidence demonstrates stimulation of fibroblasts by profibrotic cytokines, such as transforming growth factor-[beta]1, connective tissue growth factor, and endothelin-1 leads to a myofibroblastic phenotype. Myogenic markers such as [alpha]-SMA and MyoD, as well as collagen type 1, [alpha]2 have been shown to act as indicators of myofibroblastic differentiation in lung fibroblasts. Thy-1 is a cell surface glycoprotein expressed heterogeneously in fibroblast subsets which appears to function as a profibrotic suppressor. RFL-6 cells, which are endogenously Thy-1 (-), were transfected with Thy-1 or empty vector, and used in this study to determine the level of myofibroblastic differentiation based on the degree of expression of myogenic markers following the addition of profibrotic mediators. Thy-1(-) RFL-6 cells were found to have significantly higher expression levels of myogenic and myofibroblastic genes and proteins compared to the levels of expression in Thy-1 transfected fibroblasts after profibrotic cytokine stimulation. Collagen gel contraction assays were used to demonstrate increased contractility in Thy-1(-) cells, supporting the hypothesis that cells lacking Thy-1 expression have a stronger myofibroblastic phenotype, and Thy-1 inhibits myofibroblastic differentiation

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