Origin of neointimal smooth muscle: we've come full circle.

The origin of smooth muscle cells (SMCs) in atherosclerotic lesions has been a hotly debated topic for more than four decades. Until recently, it was widely accepted that the majority of smooth muscle cells in atherosclerotic lesions originate from the medial layer of the vessel wall, with local SMC proliferation and migration leading to remodeling of the vessel wall and vessel lumen.1,2 Recent reports in the literature, however, claimed that SMCs in atherosclerotic lesions originate primarily from circulating bone marrow progenitor cells.3,4 Where these cells originate from is not merely academic, because the cells that give rise to SMCs within atherosclerotic lesions would likely serve as targets for current and future therapeutic interventions. The bone marrow–derived origin suggested by these articles would indicate that attempts to control SMC phenotype in in-stent restenosis, transplant atherosclerosis, or fibrous cap rupture should be targeted toward these cells from the marrow. However, we cautioned in 2004 that if anything, the bone marrow–derived intimal SMC paradigm was “Lost in Transdifferentiation”,5 and further studies were needed to clearly resolve this critically important issue.