부산대학교 도서관

Atherosclerosis is the process underlying heart attack and stroke. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of de-differentiated vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multi-color lineage tracing models to confirm that the mature SMC can give rise to a ?stem-like? cell that is not only hyperproliferative, but also proinflammatory given its ability to produce complement-dependent anaphylatoxins. Despite being extensively opsonized with pro-phagocytic complement fragments, we find that this cell also escapes immune surveillance, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect occurs due to the non-canonical upregulation and redistribution of so-called ?don?t eat-me? molecules on inflamed phagocytes, which impairs the functionality of their complement receptors and reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the responsible anti-phagocytic molecule, CD47, restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the ?atherosclerotic stem cell? may represent a new translational target, similar to current oncology efforts directed against the cancer stem cell.