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BACKGROUND: Smooth muscle cell (SMC) accumulation in the intima of vessels is a key event in the pathogenesis of transplant atherosclerosis. The traditional hypothesis that SMCs in the lesion are derived from the media of the donor vessel has been challenged by recent observations, but the cell origin is still not well established. METHODS AND RESULTS: Here, we use a simplified model of artery allografts in transgenic mice to clearly identify the source of SMCs in transplant atherosclerosis. Aortic segments donated by BALB/c mice allografted to ROSA26 (C57B/6) mice expressing beta-galactosidase (gal) in all tissues showed that neointimal cells derived exclusively from host cells. It was also demonstrated that SMCs of neointimal and atherosclerotic lesions in vessels allografted to mice expressing beta-gal only in SMCs (SM-LacZ) or to apoE-deficient/SM-LacZ mice originated from the recipient, and not donor vessels. Interestingly, bone marrow transplantation of SM-LacZ beta-gal-expressing cells into aortic allograft recipients revealed completely negative beta-gal staining of neointimal and atherosclerotic lesions. However, a population of beta-gal-positive cells in lesions of allografts was observed in chimeric mice with ROSA26 beta-gal-expressing marrow cells. When bone marrow cells from both ROSA26 and SM-LacZ mice were cultured and stimulated with platelet-derived growth factor-BB, alpha-actin and beta-gal double-positive cells were found, suggesting that bone marrow cells have an ability to differentiate into SMCs. CONCLUSIONS: Thus, we provide strong evidence that SMCs of neointimal and atherosclerotic lesions in allografts are derived from the recipients and that non-bone marrow-derived progenitor cells are a possible source of SMCs in atherosclerotic lesions.