776 Circulation Research March 3, 2017 matrix components within the fibrous cap). Although the extracellular matrix–producing cells within the fibrous cap have been assumed to be primarily SMC derived, only recently have rigorous lineage-tracing studies from our laboratory9, 10 and others11 provided compelling evidence that SMC play a critical role in lesion pathogenesis. However, contrary to dogma, they may not always perform beneficial roles. By using SMC lineage-tracing Myh11 ERT2Cre eYFP ApoE−/− mice fed 18 weeks of Western diet to induce advanced atherosclerotic lesions, we have shown that (1)> 80% of SMC-derived cells lack detectable Acta2 expression and (2)> 30% of Lgals3+ cells are SMC derived in both mouse and human lesions. 9 By combining lineage tracing with simultaneous SMC-specific gene knockout of pluripotency factors Klf4 or Oct4, we have shown that SMC can play a critical role in the pathogenesis of late-stage lesions, which can be either atheroprotective or atheropromoting depending on the nature of their phenotypic transitions. For example, Klf4-dependent transitions, including formation of SMC-derived macrophage-marker+ foam cells, 9 exacerbated lesion pathogenesis, whereas Oct4-dependent transitions were atheroprotective, being required for migration and stable investment of SMC into the fibrous cap. 10 Taken together, these results highlight the critical importance of identifying factors and mechanisms that promote plaque stabilizing atheroprotective changes within SMC and other major cell types within lesions and therapeutic approaches that can induce such changes. The findings also highlight the importance of lineage tracing in atherosclerosis. Because of significant plasticity in multiple lesion cell types, there is substantial ambiguity in cell identification when using traditional markers (eg, Acta2, CD68, and CD31), which can only be overcome by the use of rigorous lineage-tracing techniques.