Hypercholesterolemia Tunes Hematopoietic Stem/Progenitor Cells for Inflammation and Atherosclerosis

Abstract

As the pathological basis of cardiovascular disease (CVD), atherosclerosis is featured as a chronic inflammation. Hypercholesterolemia is an independent risk factor for CVD. Accumulated studies have shown that hypercholesterolemia is associated with myeloid cell expansion, which stimulates innate and adaptive immune responses, strengthens inflammation, and accelerates atherosclerosis progression. Hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM) expresses a panel of lipoprotein receptors to control cholesterol homeostasis. Deficiency of these receptors abrogates cellular cholesterol efflux, resulting in HSPC proliferation and differentiation in hypercholesterolemic mice. Reduction of the cholesterol level in the lipid rafts by infusion of reconstituted high-density lipoprotein (HDL) or its major apolipoprotein, apoA-I, reverses hypercholesterolemia-induced HSPC expansion. Apart from impaired cholesterol metabolism, inhibition of reactive oxygen species production suppresses HSPC activation and leukocytosis. These data indicate that the mechanisms underlying the effects of hypercholesterolemia on HSPC proliferation and differentiation could be multifaceted. Furthermore, dyslipidemia also regulates HSPC-neighboring cells, resulting in HSPC mobilization. In the article, we review how hypercholesterolemia evokes HSPC activation and mobilization directly or via its modification of BM microenvironment. We hope this review will bring light to finding key molecules to control HSPC expansion, inflammation, and atherosclerosis for the treatment of CVD.

Keywords: atherosclerosis; cholesterol efflux; hematopoietic stem/progenitor cells; hypercholesterolemia; reactive oxygen species.

Figure 1

The effects of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) on hematopoietic stem/progenitor cell (HSPC) expansion and differentiation. Lineage^- Sca-1⁺ cKit⁺ cells were sorted out by fluorescence-activated cell sorting (FACS) and cultured in serum-free medium in the presence of BSA (A); granulocyte-macrophage colony-stimulating factor (GM-CSF) (B); or LDL (C); and LDL plus HDL (D) for 14 days and then collected by cytospin for Giemsa staining. Red arrow indicates quiescent HSPC; black arrow indicates promonocytes; blue arrow indicates granulocytes. Scale bar: 20 μm. Adapted from Feng et al, PLoS ONE 2012.

Figure 2

The mechanisms underlying the impact of hypercholesterolemia on HSPC. Under normocholesterolemia, ATP-binding cassette transporter (ABCA1), ATP-binding cassette sub-family G member 1(ABCG1), and scavenger receptor type B-I (SR-BI) facilitate cholesterol efflux. After secretion, apolipoprotein E (apoE) binds to heparin sulfate proteoglycans (HSPG) for cholesterol removal. Furthermore, apoE and apoE-containing HDL interact with ABCA1 and ABCG1 for reverse cholesterol transport. apoE, ABCA1, and ABCG1 expression are regulated by liver X receptor (LXR). HDL acts via SR-BI to control Akt and p38 mitogen-activated protein kinases (p38MAPK) phosphorylation and reactive oxygen species (ROS) production. As the net result, cholesterol homeostasis is maintained in HSPC. Deficiency of ABCA1, ABCG1, apoE, and SR-BI disrupts cholesterol efflux. Hypercholesterolemia accelerates impaired cholesterol efflux, leading to enriched cholesterol accumulation in the lipid raft. Thus, the expression of the common β subunit of the IL-3/GM-CSF receptors is increased, resulting in elevated response to IL-3 and GM-CSF for HSPC proliferation. In parallel, SR-BI deficiency abrogates the regulation of HDL on ROS production. Therefore, HSPC are activated for proliferation and differentiation. The skewed HSPC differentiation to myeloid cells produces IL-3 and GM-CSF that further potentiate HSPC activation. pERK, phosphorylated extracellular signal-regulated kinase; pSTAT5, phosphorylated signal transducer and activator of transcription 5.