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Summary Adventitial progenitor cells, including SCA-1+ and mesenchymal stem cells, are believed to be important in vascular remodeling. It has been shown that SCA-1+ progenitor cells are involved in neointimal hyperplasia of vein grafts, but little is known concerning their involvement in hyperlipidemia-induced atherosclerosis. We employed single-cell sequencing technology on primary adventitial mouse SCA-1+ cells from wild-type and atherosclerotic-prone (ApoE-deficient) mice and found that a group of genes controlling cell migration and matrix protein degradation was highly altered. Adventitial progenitors from ApoE-deficient mice displayed an augmented migratory potential both in vitro and in vivo. This increased migratory ability was mimicked by lipid loading to SCA-1+ cells. Furthermore, we show that lipid loading increased miRNA-29b expression and induced sirtuin-1 and matrix metalloproteinase-9 levels to promote cell migration. These results provide direct evidence that blood cholesterol levels influence vascular progenitor cell function, which could be a potential target cell for treatment of vascular disease., Highlights • Hyperlipidemia affects migration of AdvSca-1+ cells • AdvSca-1+ ApoE KO cells show altered matrix of proteins • Decorin ameliorates extensive migration of AdvSca-1+ cells toward the neointima • MicroRNA-29 interferes with AdvSca-1+ migration via SIRT-1 and MMP-9, In this article, Xu and colleagues show that hyperlipidemia may confer to neointimal formation by extensive mobilization of adventitial progenitors. Using the ApoE KO murine model, they show that increased cholesterol levels augment adventitia progenitor migration, both in vitro and in vivo, through a modified matrix of proteins. Migratory capability could be ameliorated through mechanisms involving collagen formation and microRNA inhibition.