ATP-Binding Cassette Transporters and HDL Suppress Hematopoietic Stem Cell Proliferation

Abstract

Elevated leukocyte cell numbers (leukocytosis), and monocytes in particular, promote atherosclerosis; however, how they become increased is poorly understood. Mice deficient in the adenosine triphosphate-binding cassette (ABC) transporters ABCA1 and ABCG1, which promote cholesterol efflux from macrophages and suppress atherosclerosis in hypercholesterolemic mice, displayed leukocytosis, a transplantable myeloproliferative disorder, and a dramatic expansion of the stem and progenitor cell population containing Lin − Sca-1 + Kit + (LSK) in the bone marrow.

Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells

“…HSC numbers were increased 1.5‐fold, accompanied by increases in myeloid progenitor populations (common myeloid progenitors, megakaryocyte‐erythrocyte progenitors, and GM progenitors), in the Lxr αβ −/− mice compared with their WT counterparts (Figure 1A). These changes are consistent with previous reports in which absence of the LXR target genes, Abca1 and Abcg1 or Apoe , allows for proliferation of the upstream HSCs and expansion of the myeloid progenitor cell populations 37, 38. There was no significant change in BM EPC numbers (Figure 1A), whereas in circulation, EPC numbers were reduced by 27% in the Lxr αβ −/− compared with WT mice (Figure 1B).…”

“…Increased cholesterol content of HSCs has been previously demonstrated to increase their proliferation, leading to monocytosis 37, 38, 46. Herein, we have shown that WD feeding also increases the cholesterol content and proliferation of HSCs in Lxr αβ −/− mice (Figure 4C), not only pushing the fate of these HSCs towards the myeloid population but also away from the formation of EPCs (Figure 3A and 3B), suggesting that LXRs play a basal role in hematopoietic differentiation within the individual lineages.…”

“…Although studies using knockout mice for the LXR target genes Abca1/g1 −/− or Apoe −/− have shown important roles for cholesterol in the development of monocytosis,37, 38 a role for LXRs per se in regulating global hematopoiesis, particularly within a hypercholesterolemic environment, has not been explored. Likewise, to our knowledge, quantitation of EPCs relative to other hematopoietic cell types has also not yet been investigated in any of these contexts.…”

“…One hypothesis, consistent with previous studies performed in mouse models absent LXR target genes, is that LXRs influence the subcellular distribution of cholesterol within EPCs. Indeed, Apoe −/− and Abca1/g1 −/− mice were shown to have an increase in cholesterol accumulation within lipid rafts of HSCs, leading to increased signaling through the common β subunit to enhance the production of myeloid cells 37, 38. In contrast, other studies demonstrated that LXR agonist treatment disrupted the localization of key signaling molecules vascular endothelial growth factor receptor 2 and protein kinase B within lipid rafts, suggesting that activation of LXRs decreases the intracellular distribution of cholesterol to the rafts 49, 50.…”

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

“…Transgenic studies revealed that ABCA1/ABCG1 gene–deficient mice fed an HFD had an expanded pool of hematopoietic stem/progenitor cells, resulting in monocytosis by directly producing blood monocytes or mobilizing to the spleen and initiating extramedullary hematopoiesis 66. Increased circulating monocytes enter the atheroma, differentiate into macrophages, and promote atherogenesis 66.…”