Enhancing Cholesterol Efflux Pathways Suppresses Hematopoietic Stem Cell Proliferation And Monocytosis In Apoe-/- Mice

Atherosclerosis is associated with monocytosis and attenuating monocytosis results in a reduction in atherosclerosis. Mice deficient in ABCA1 and ABCG1 have leukocytosis and monocytosis that is reversed by Increased HDL levels (human apoA-I transgene) which promotes cholesterol efflux and reduces the proliferation of hematopoietic stem and progenitor cells (HSPCs). Apoe−/− mice also have monocytosis that is associated with expansion of the HSPC population. We hypothesized that promotion of cholesterol efflux from HSPCs in WTD-fed apoE−/− mice, by infusion of rHDL or treatment with LXR activators to up-regulate ABCA1/G1 would suppress HSPC proliferation and monocytosis. A dose response study (40, 80, 120mg/kg) revealed that rHDL (CSL-111) suppressed leukocytosis, monocytosis and proliferation of HSPCs with maximum effect at 80mg/kg, similar to doses previously shown to be effective in human IVUS studies. Treatment with LXR activator (20mg/kg X 3) also resulted in decreased leukocytosis, monocytosis and HSPC proliferation, and administration of rHDL+LXR activator produced larger reductions in these parameters than either treatment alone. Interestingly, circulating cells were only slightly reduced (to pre-WTD levels) in WT mice, with no changes observed in HSPCs. As IL-3 drives proliferation of HSPCs we examined the IL-3 common β-subunit (IL-3βR) expression in HSPCs. We discovered that apoE−/− mice have an increased population of IL-3βR+ HSCs compared to WT mice (apoE−/−:9.6% vs WT:5.4% P