Activation of the ESC pluripotency factor OCT4 in smooth muscle cells is atheroprotective

There are controversial claims that the embryonic stem cell (ESC) pluripotency factor OCT4 is activated in somatic cells, but there is no evidence it plays a functional role in these cells. Herein we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 within Apoe(−/−) mice resulted in increased lesion size and changes consistent with decreased plaque stability including a thinner fibrous cap, increased necrotic core, and increased intra-plaque hemorrhage. Results of SMC-lineage tracing studies showed that these changes were likely due to marked reductions in SMC number within lesions including impaired SMC migration and investment within the fibrous cap. Re-activation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was HIF1α- and KLF4-dependent. Results provide the first direct evidence that OCT4 plays a functional role in somatic cells and highlight the importance of further investigation of possible OCT4 functions in normal and diseased somatic cells.