Abstract
RationaleHematopoietic stem/progenitor cells (HSPC) are responsible for maintaining the blood system as a result of their self-renewal and multilineage differentiation capacity. Recently, studies have suggested that HDL cholesterol may inhibit and impaired cholesterol efflux may increase HSPC proliferation and differentiation.ObjectivesWe hypothesized that LDL may enhance HSPC proliferation and differentiation while HDL might have the opposing effect which might influence the size of the pool of inflammatory cells.Methods and ResultsHSPC number and function were studied in hypercholesterolemic LDL receptor knockout (LDLr−/−) mice on high fat diet. Hypercholesterolemia was associated with increased frequency of HSPC, monocytes and granulocytes in the peripheral blood (PB). In addition, an increased proportion of BM HSPC was in G2M of the cell cycle, and the percentage of HSPC and granulocyte-macrophage progenitors (GMP) increased in BM of LDLr−/− mice. When BM Lin-Sca-1+cKit+ (i.e. “LSK”) cells were cultured in the presence of LDL in vitro we also found enhanced differentiation towards monocytes and granulocytes. Furthermore, LDL promoted lineage negative (Lin−) cells motility. The modulation by LDL on HSPC differentiation into granulocytes and motility was inhibited by inhibiting ERK phosphorylation. By contrast, when mice were infused with human apoA-I (the major apolipoprotein of HDL) or reconstituted HDL (rHDL), the frequency and proliferation of HSPC was reduced in BM in vivo. HDL also reversed the LDL-induced monocyte and granulocyte differentiation in vitro.ConclusionOur data suggest that LDL and HDL have opposing effects on HSPC proliferation and differentiation. It will be of interest to determine if breakdown of HSPC homeostasis by hypercholesterolemia contributes to inflammation and atherosclerosis progression.
Highlights
Lipoproteins play essential roles in coronary heart disease (CHD)
It will be of interest to determine if breakdown of Hematopoietic stem/progenitor cells (HSPC) homeostasis by hypercholesterolemia contributes to inflammation and atherosclerosis progression
We further demonstrated that exposure of HSPC to LDL in vitro induced differentiation to monocytes and granulocytes, whereas HDL decreased myeloid cell differentiation induced by LDL
Summary
Lipoproteins play essential roles in coronary heart disease (CHD). A meta-analysis showed that a 1 mmol/l reduction in the level of LDL cholesterol is associated with 19% reduction in CHD mortality [1]. Increase of HDL cholesterol by 1 mg/dl decreases the incidence of CHD 2–3% [2]. Apart from CHD, hypercholesterolemia accelerates other diseases including Alzheimer’s amyloid pathology [3]. Atherosclerosis, the underlying pathogenesis of CHD, is characterized by chronic inflammation due to both loss of endothelial integrity and to subendothelial retention of LDL [4]. Once retained in the subendothelial space, both native and modified LDL activate vascular cells, attracting circulating white blood cells to form plaques
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