Abstract 603: Nestin+ Cells Regulate Bone Marrow Egress of Inflammatory Cells and Their Infiltration in the Aorta in Atherosclerosis
Atherosclerosis is a chronic inflammatory disease of the artery wall and represents the leading death cause in developed countries. Endothelial cells and smooth muscle cells participate in atherogenesis, but it is unclear whether other mesenchymal cells in the bone marrow and/or the artery wall contribute to this process. We have recently identified mesenchymal stem cells with niche functions for haematopoietic stem cells in the bone marrow, based on the expression of the intermediate filament protein nestin (Méndez-Ferrer S et al. Nature 2010). Some nestin+ cells also cooperate with endothelial cells in directing the egress of pro-inflammatory monocytes from the bone marrow to circulation in response to peripheral infections (Shi C at el. Immunity 2011). However, it remains unknown whether nestin+ cells regulate the migration of inflammatory cells in a chronic inflammatory disease, such as atherosclerosis. Also, some endothelial cells express nestin (Isern J et al. eLife 2014), but it remains unclear whether they have a specialized function. We found that nestin+ cells residing in the adventitia of adult mouse aorta increased more than 30 times in apolipoprotein E (ApoE) KO mice fed with high fat diet and contributed to endothelial cells in the atheroma plaque. In this mouse model, deletion of monocyte chemoattractant protein-1 (Mcp1) in nestin+ cells (using Nestin-creERT2;Mcp1-floxed mice), but not in endothelial cells (using Cdh5-creERT2;Mcp1-floxed mice), led to increased number of pro-inflammatory monocytes and neutrophils in circulation. Surprisingly, the number of inflammatory cells in the aorta of these mice was reduced. Adoptive transfer experiments confirmed that Mcp1 secreted by nestin+ cells within the artery wall is required for the initial infiltration of pro-inflammatory monocytes and neutrophils during atherogenesis. As a result, mice lacking Mcp1 in nestin+ cells -but not in endothelial cells only- had reduced inflammatory infiltration in the aorta, delayed atheroma plaque formation, less calcified aortas (μCT) and reduced calcium deposits in the aortic valves. These results suggest that nestin expression marks stromal cells that regulate inflammatory cell migration in atherosclerosis.
Author Disclosures: R. Del Toro: None. S. Mendez-Ferrer: None.
- © 2015 by American Heart Association, Inc.