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Blood. 2010 May 13;115(19):3886-94. doi: 10.1182/blood-2009-08-240580. Epub 2009 Dec 15.

Hypercholesterolemia promotes bone marrow cell mobilization by perturbing the SDF-1:CXCR4 axis.

Author information

1
Angiogenesis Group, Instituto Português de Oncologia de Francisco Gentil, Centro de Lisboa, EPE (CIPM/IPOLFG), Lisboa, Portugal. sergidias@ipolisboa.min-saude.pt

Erratum in

  • Blood. 2011 Nov 3;118(18):5060.

Abstract

Hypercholesterolemia is associated with elevated peripheral blood leukocytes and increased platelet levels, generally attributed to cholesterol-induced proinflammatory cytokines. Bone marrow (BM) cell mobilization and platelet production is achieved by disrupting the SDF-1:CXCR4 axis, namely with granulocyte colony-stimulating factor and/or CXCR4 antagonists. Here we show that high cholesterol disrupts the BM SDF-1:CXCR4 axis; promotes the mobilization of B cells, neutrophils, and progenitor cells (HPCs); and creates thrombocytosis. Hypercholesterolemia was achieved after a 30-day high-cholesterol feeding trial, resulting in elevated low-density lipoprotein (LDL) cholesterol levels and inversion of the LDL to high-density lipoprotein cholesterol ratio. Hypercholesterolemic mice displayed lymphocytosis, increased neutrophils, HPCs, and thrombocytosis with a lineage-specific decrease in the BM. Histologic analysis revealed that megakaryocyte numbers remained unaltered but, in high-cholesterol mice, they formed large clusters in contact with BM vessels. In vitro, LDL induced stromal cell-derived factor-1 (SDF-1) production, suggesting that megakaryocyte delocalization resulted from an altered SDF-1 gradient. LDL also stimulated B cells and HPC migration toward SDF-1, which was blocked by scavenger receptor class B type I (cholesterol receptor) inhibition. Accordingly, hypercholesterolemic mice had increased peripheral blood SDF-1 levels, increased platelets, CXCR4-positive B lymphocytes, neutrophils, and HPCs. High cholesterol interferes with the BM SDF-1:CXCR4 axis, resulting in lymphocytosis, thrombocytosis, and HPC mobilization.

PMID:
20009035
DOI:
10.1182/blood-2009-08-240580
[Indexed for MEDLINE]
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