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Aim: To explore this hypothesis that smooth muscle cells may be capable of acquiring a myofibroblastic phenotype, we have studied the expression of smoothelin in fibrotic conditions., Methods: Normal liver tissue (n = 3) was obtained from macroscopically normal parts of hepatectomy, taken at a distance from hemangiomas. Pathological specimens included post-burn cutaneous hypertrophic scars (n = 3), fibrotic liver tissue (n = 5), cirrhotic tissue (viral and alcoholic hepatitis) (n = 5), and hepatocellular carcinomas (n = 5). Tissue samples were fixed in 10% formalin and embedded in paraffin for immunohistochemistry or were immediately frozen in liquid nitrogen-cooled isopentane for confocal microscopy analysis. Sections were stained with antibodies against smoothelin, which is expressed exclusively by smooth muscle cells, and α-smooth muscle actin, which is expressed by both smooth muscle cells and myofibroblasts., Results: In hypertrophic scars, α-smooth muscle actin was detected in vascular smooth muscle cells and in numerous myofibroblasts present in and around nodules, whereas smoothelin was exclusively expressed in vascular smooth muscle cells. In the normal liver, vascular smooth muscle cells were the only cells that express α-smooth muscle actin and smoothelin. In fibrotic areas of the liver, myofibroblasts expressing α-smooth muscle actin were detected. Myofibroblasts co-expressing α-smooth muscle actin and smoothelin were observed, and their number was slightly increased in parallel with the degree of fibrosis (absent in liver with mild or moderate fibrosis; 5% to 10% positive in liver showing severe fibrosis). In cirrhotic septa, numerous myofibroblasts co-expressed α-smooth muscle actin and smoothelin (more than 50%). In hepatocellular carcinomas, the same pattern of expression for α-smooth muscle actin and smoothelin was observed in the stroma reaction surrounding the tumor and around tumoral cell plates. In all pathological liver samples, α-smooth muscle actin and smoothelin were co-expressed in vascular smooth muscle cells., Conclusion: During development of advanced liver fibrosis, a subpopulation of myofibroblasts expressing smoothelin may be derived from vascular smooth muscle cells, illustrating the different cellular origins of myofibroblasts.