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

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 colonystimulating 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 highcholesterol 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. (Blood. 2010;115(19):3886-3894) IntroductionBone marrow (BM) cells have a well-defined and consistent lineage-specific spatial distribution of hematopoietic progenitor (HPC) and maturing cells, mainly between 2 locations, also termed niches: the endosteal and the vascular niche. 1-3 The BM endosteal niche, which mainly lodges the stem cell population, is located in the inner surface of the bone. 1 The BM vascular niche is represented by the BM sinusoidal microvasculature with adjacent megakaryocytes (MKs) 4 and surrounding hematopoietic cells (HCs) and allows the exit of mature HCs to the peripheral blood (PB), being the site where HPCs differentiate and set the stage for full reconstitution of hematopoiesis after BM ablation. 2 External stimuli, which alter hematologic parameters, act most likely by disturbing the homeostasis of the BM niches, thereby interfering with the spatial distribution of HCs. Namely, increased systemic cholesterol levels (hypercholesterolemia) are known to induce endothelial activation by increased expression of adhesion molecules and the release of proinflammatory cytokines, which are believed to result in leukocyte recruitment 3,5,6 and may explain the leukocytosis observed in patients with hypercholesterolemia. 7 However, in patients with hypercholesterolemia, thrombocytosis (high platelet count) is a common finding, and MKs were shown to be altered. [7][8][9...

Hypercholesterolemia and its association with enhanced stem cell mobilization and harvest after high-dose cyclophosphamide+G-CSF

“…The median CD34 þ cell counts in the PB on days 6-17 after standard mobilization are depicted in Figure 1b and showed significantly higher levels on day 12 (88.5 (43-145) vs 14 (3-71)/mL, P ¼ 0.005) and on day 13 (91 (26-174)/mL vs 20 (2.5-65)/mL, P ¼ 0.002). This clinical data is in high accordance with the publication by Gomes et al 13 in the mouse that could show a major effect of a high-cholesterol diet on the number of circulating progenitor cells. They demonstrated that hypercholesterolemia induced SDF-1 secretion resulting in elevated SDF-1 plasma levels inducing CXCR4 þ -progrenitor cells exit into the PB.…”

“…They demonstrated that hypercholesterolemia induced SDF-1 secretion resulting in elevated SDF-1 plasma levels inducing CXCR4 þ -progrenitor cells exit into the PB. 13 In addition, our patient cohort received chemotherapy with cyclophosphamide in combination with G-CSF, which is known to manipulate the SDF-1/CXCR4-interaction as well. 9 Accordingly, the median overall number of Hypercholesterolemia enhanced stem cell mobilization M Crysandt et al harvested CD34 þ cells was higher in patients with hypercholesterolemia (819.5 (553.2-1125.5) vs 533.5 (424.2-718.6)  10 6 , P ¼ 0.024, adjusted to body weight: 9.6 (7.1-15.0) vs 7.4 (5.4-9.1)  10 6 /kg, Po0.001) and a sufficient number for at least one SCT (more than 2.0 CD34 þ cells  10 6 /kg) was achieved in a remarkably higher proportion (84.9 vs 52.9%, P ¼ 0.004).…”

“…9 However, only a few factors affecting stem cell mobilization and harvest are known so far. [10][11][12] Very recently, Gomes et al 13 identified hypercholesterolemia to promote stem cell mobilization in mice by also disrupting the SDF-1/CXCR4 axis.…”

Stromal Cell-Derived Factor-1α as a Novel Biomarker for Hyperlipidemia

“…3C). Taken together, these data suggest that logSDF-1α levels are higher in male patients with BHLP, which is accompanied by higher LDL-C (Gomes et al 2010) and normal ranges of HDL-C. Moreover, logSDF-1α levels in male patients with HLP are lower, which is accompanied by slightly higher LDL-C and lower HDL-C.…”

“…Experiments on mice with induced hypercholesterolemia strongly suggest that elevated cholesterol levels, specifically elevated LDL, interfere with the SDF-1-CXCR4 axis in the bone marrow (BM) microenvironment and affect BM homeostasis. This may explain the increased peripheral blood (PB) levels of SDF-1, CXCR4-positive B lymphocytes, neutrophils, and progenitor cells in hypercholesterolemic mice (Gomes et al 2010). However, whether serum SDF-1α levels, as well as expression of the SDF-1α receptor CXCR4 on PBMCs and white blood cells, are altered in hyperlipidemia patients remains unknown.…”