Hypercholesterolemia-induced priming of hematopoietic stem and progenitor cells aggravates atherosclerosis.
Modulation of hematopoietic stem and progenitor cells (HSPCs) determines immune cell function. In this study, we investigated how hypercholesterolemia affects HSPC biology and atherosclerosis. Hypercholesterolemia induced loss of HSPC quiescence, characterized by increased proliferation and expression of cyclin B1, C1, and D1, and a decreased expression of Rb, resulting in a 3.6- fold increase in the number of HSPCs in hypercholesterolemic Ldlr(-/-) mice. Competitive bone marrow (BM) transplantations showed that a hypercholesterolemic BM microenvironment activates HSPCs and skews their development toward myeloid lineages. Conversely, hypercholesterolemia-primed HSPCs acquired an enhanced propensity to generate myeloid cells, especially granulocytes and Ly6C(high) monocytes, even in a normocholesterolemic BM microenvironment. In conformity, macrophages differentiated from hypercholesterolemia-primed HSPCs produced 17.0% more TNF-α, 21.3% more IL-6, and 10.5% more MCP1 than did their normocholesterolemic counterparts. Hypercholesterolemia-induced priming of HSPCs generated leukocytes that more readily migrated into the artery, which resulted in a 2.1-fold increase in atherosclerotic plaque size. In addition, these plaques had a more advanced phenotype and exhibited a 1.2-fold increase in macrophages and 1.8-fold increase in granulocytes. These results identify hypercholesterolemia-induced activation and priming of HSPCs as a novel pathway in the development of atherosclerosis. Inhibition of this proinflammatory differentiation pathway on the HSPC level has the potential to reduce atherosclerosis.
1Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 15, 1105 CZ Amsterdam, The Netherlands. e.lutgens@amc.uva.nl.
Tom
T
Seijkens
Marten A
MA
Hoeksema
Linda
L
Beckers
Esther
E
Smeets
Svenja
S
Meiler
Johannes
J
Levels
Marc
M
Tjwa
Menno P J
MP
de Winther
Esther
E
Lutgens
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002478:Cells, Cultured; D006098:Granulocytes / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006937:Hypercholesterolemia / Q000378:metabolism*; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D008074:Lipoproteins; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha
inflammation; lipoproteins