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High levels of blood leukocytes, which are inflammatory cells, are associated with an increased cardiovascular risk in humans. Also, after myocardial infarction, increased levels of leukocytes predict an increased risk of re-infarction and death.

Leukocytes commonly originate from stem and progenitor cells in the bone marrow, but they can under certain conditions also be produced by stem and progenitor cells in the spleen, a process referred to as extramedullary hematopoiesis. Stem and progenitor cells have mobilized to the spleen from the bone marrow in a process called stem and progenitor cell mobilization. Under healthy conditions, stem and progenitor cells are being kept in the bone marrow by factors produced in the bone marrow microenvironment.

Our recently published paper (1) shows that pathways that mediate cholesterol efflux from peripheral cells to high-density-lipoprotein prevent stem and progenitor cell mobilization. Our experiments in mouse models reveal that disruption of these cholesterol efflux pathways in macrophages and dendritic cells leads to cholesterol accumulation and subsequent release of inflammatory factors. As a result, other cell types are stimulated to produce growth factors. These growth factors disrupt the bone marrow microenvironment, facilitating mobilization of stem and progenitor cells rather than keeping them in the bone marrow. As a consequence, stem and progenitor cells appear in the blood and subsequently mobilize to the spleen, where they give rise to leukocytes. It has been shown that leukocytes originating from the spleen can infiltrate atherosclerotic lesions in mice, thus increasing the risk for cardiovascular disease. Another recently published study (2) showed that stem and progenitor cell mobilization is increased in mice after an experimental heart attack, also increasing the risk for cardiovascular disease.

In our study (1), we showed that injections of high-density-lipoprotein suppress stem and progenitor cell mobilization in mouse models carrying a mutation facilitating it. Thus, high-density-lipoprotein mediated cholesterol efflux prevents stem and progenitor cell mobilization. Although recent clinical trials raised the question whether raising high-density-lipoprotein is still a valid therapeutic target for cardiovascular disease (3) of our studies suggest that high-density-lipoprotein is protective when it is functional in terms of its cholesterol efflux mediating capacity.

1. Westerterp M, Gourion-Arsiquaud S, Murphy AJ, Shih A, Cremers S, Levine RL, Tall AR, Yvan-Charvet L. Regulation of hematopoietic stem and progenitor cell mobilization by cholesterol efflux pathways. Cell Stem Cell 2012: 195-206.

2. Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HW, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M. Myocardial infarction accelerates atherosclerosis. Nature 2012: 325-329.

3. Rader DJ and Tall AR. The not-so-simple HDL story: Is it time to revise the HDL cholesterol hypothesis? Nature Medicine 2012: 1344-1346.

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