Extramedullary Hematopoiesis Generates Ly-6C Monocytes That Infiltrate Atherosclerotic Lesions

Background—Atherosclerotic lesions are believed to grow via the recruitment of bone marrow–derived monocytes. Among the known murine monocyte subsets, Ly-6C monocytes are inflammatory, accumulate in lesions preferentially, and differentiate. Here, we hypothesized that the bone marrow outsources the production of Ly-6C monocytes during atherosclerosis. Methods and Results—Using murine models of atherosclerosis and fate-mapping approaches, we show that hematopoietic stem and progenitor cells progressively relocate from the bone marrow to the splenic red pulp, where they encounter granulocyte macrophage colony-stimulating factor and interleukin-3, clonally expand, and differentiate to Ly-6C monocytes. Monocytes born in such extramedullary niches intravasate, circulate, and accumulate abundantly in atheromata. On lesional infiltration, Ly-6C monocytes secrete inflammatory cytokines, reactive oxygen species, and proteases. Eventually, they ingest lipids and become foam cells. Conclusions—Our findings indicate that extramedullary sites supplement the hematopoietic function of the bone marrow by producing circulating inflammatory cells that infiltrate atherosclerotic lesions. (Circulation. 2012;125:364-374.)