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Tracking chromatin signatures in individual cells to trace vascular smooth muscle cell lineage in human atherosclerotic lesion (278.4)
Author(s) -
Gomez Delphine,
Shankman Laura,
Owens Gary
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.278.4
Subject(s) - biology , lesion , epigenetics , macrophage , chromatin , population , histone , lineage markers , pathology , cell , lineage (genetic) , gene , microbiology and biotechnology , phenotype , in vitro , genetics , medicine , environmental health
Atherosclerosis is a chronic disease of the arterial wall responsible for nearly 50% of deaths in developed countries. There is a strong correlation between ratio of smooth muscle cells (SMC) to macrophages and stability of atherosclerotic lesions; a high macrophage to SMC content associated with high risk of plaque rupture. Herein, we reevaluated the contribution of SMC within lesions that was underestimated due to lack of identification of SMC undergoing phenotypic switching (i.e loss of SMC marker gene expression). Using a SMC‐lineage tracing mouse, we show that traditional staining for SMC is unable to detect 86% of the SMC population within lesions of Apoe‐/‐ mice and that 25% of macrophages identified by traditional macrophage markers are of SMC origin. To validate these data in human, we developed a novel method of detection of histone modifications on gene loci in single cells using tissue sections. Our assay was based on studies showing that the histone modification H3K4dime on the SMC marker genes is a specific and stable epigenetic marker of the SMC lineage in vitro. First, H3K4dime on the SMC marker genes (PLA+ cells) was strictly restricted to SMC lineage in vivo. Then, we identified PLA+/macrophage markers+ cells in human lesions. In conclusion, we rigorously identified lesion cells of SMC origin and we provide exciting evidence that a fraction of macrophage‐like cells in human lesions are derived from SMC. Grant Funding Source : American Heart Association