Abstract 17559: Multiple Cellular Components of Atherosclerotic Plaque Originate from Mesenchymal Stem Cells
Background & Hypothesis: Atherosclerotic plaque vulnerability is primarily determined by plaque composition, which is in turn determined by the origin, abundance, and organization of various plaque components. Given the plasticity of mesenchymal stem cells (MSCs) and their presence in plaques, we speculate that MSCs can contribute to multiple cellular components of plaques.
Methods & Results: We have used immunolabeling to identify abundant NG2-positive cells in both human and ApoE null mouse plaques. Double labeling studies indicate that these cells largely fail to express endothelial (CD31), smooth muscle cell (α-smooth muscle actin), or macrophage (CD68) markers, and can be classified as immature MSCs based on their co-expression of PDGFRβ, CD146 and CD90 markers in human plaque, or PDGFRβ, endosialin and CD44 markers in mouse plaque. To explore the origin of these MSCs, we transplanted bone marrow from beta-actin-EGFP/ApoE null mice to gamma-irradiated ApoE null mice and used a high fat diet to induce atherogenesis in the chimeric mice. Immunostaining of the resulting plaques revealed abundant EGFP label in most of the macrophages, but no EGFP label in NG2-positive MSCs, showing that these progenitors are not derived from bone marrow. Instead, they must originate from local arterial sources. To determine the developmental fate of plaque MSCs, we generated an ApoE null mouse carrying an EGFP reporter (CAG-CAT-GFP) reporter driven by the PDGFRβ/Cre transgene. In these mice, the EGFP label is permanently expressed in all cells of the MSC lineage. We induced atherogenesis in these mice via distal ligation of the common carotid artery and a 4-week treatment with high fat diet. Labeling plaque sections with antibodies specific for endothelial cells, smooth muscle cells, and macrophages revealed examples of EGFP labeling in each of the three cell types. Plaque MSCs therefore contribute to all three major cellular components of plaques, and probably also to plaque vasculature.
Summary & Significance: Plaque MSCs can contribute to multiple cellular components of plaques. Elucidating the involvement of MSCs in the formation, composition, and stability of plaques may facilitate development of novel therapeutic approaches based on manipulation of MSC fate.
- © 2010 by American Heart Association, Inc.