ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice
Andrew J. Murphy, … , Laurent Yvan-Charvet, Alan R. Tall
Andrew J. Murphy, … , Laurent Yvan-Charvet, Alan R. Tall
Published September 26, 2011
Citation Information: J Clin Invest. 2011;121(10):4138-4149. https://doi.org/10.1172/JCI57559.
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Research Article

ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice

Abstract

Leukocytosis is associated with increased cardiovascular disease risk in humans and develops in hypercholesterolemic atherosclerotic animal models. Leukocytosis is associated with the proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) in mice with deficiencies of the cholesterol efflux–promoting ABC transporters ABCA1 and ABCG1 in BM cells. Here, we have determined the role of endogenous apolipoprotein-mediated cholesterol efflux pathways in these processes. In Apoe–/– mice fed a chow or Western-type diet, monocytosis and neutrophilia developed in association with the proliferation and expansion of HSPCs in the BM. In contrast, Apoa1–/– mice showed no monocytosis compared with controls. ApoE was found on the surface of HSPCs, in a proteoglycan-bound pool, where it acted in an ABCA1- and ABCG1-dependent fashion to decrease cell proliferation. Accordingly, competitive BM transplantation experiments showed that ApoE acted cell autonomously to control HSPC proliferation, monocytosis, neutrophilia, and monocyte accumulation in atherosclerotic lesions. Infusion of reconstituted HDL and LXR activator treatment each reduced HSPC proliferation and monocytosis in Apoe–/– mice. These studies suggest a specific role for proteoglycan-bound ApoE at the surface of HSPCs to promote cholesterol efflux via ABCA1/ABCG1 and decrease cell proliferation, monocytosis, and atherosclerosis. Although endogenous apoA-I was ineffective, pharmacologic approaches to increasing cholesterol efflux suppressed stem cell proliferative responses.

Authors

Andrew J. Murphy, Mani Akhtari, Sonia Tolani, Tamara Pagler, Nora Bijl, Chao-Ling Kuo, Mi Wang, Marie Sanson, Sandra Abramowicz, Carrie Welch, Andrea E. Bochem, Jan Albert Kuivenhoven, Laurent Yvan-Charvet, Alan R. Tall

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Figure 4

Cellular cholesterol levels modulate HSPC proliferation through the CBS.

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Cellular cholesterol levels modulate HSPC proliferation through the CBS....
(A) WT and Apoe–/– mice were fed a WTD for 4 weeks and infused with saline or rHDL (80 mg/kg). 96 hours after infusion, HSPCS were isolated via flow cytometry and stained with CTx-B for lipid rafts. HSPCs were viewed on a confocal microscope, and lipid raft abundance was quantified. Scale bars: 5 μM. (B–D) WT and Apoe–/– mice were fed a WTD for 4 weeks, and BM HSPCs were analyzed by flow cytometry. (B) In vivo HSPC proliferation, determined by injecting mice with EdU 18 hours prior to sacrifice and assessing EdU incorporation into DNA. (C) Percent HSPCs expressing the CBS. (D) Phospho-flow for p-ERK1/2 and p-STAT5 in HSPCs. *P < 0.05, **P < 0.01 vs. WT; ^^P < 0.01 vs. Apoe–/– plus saline. (E) BM was isolated from WT and Apoe–/– mice and incubated with IL-3 and GM-CSF in the presence or absence of cholesterol-loaded CyD (Chol-CyD; 6.6 mg/ml), CyD (6.6 mg/ml), or rHDL (1 mg/ml), and proliferation was assessed by [3H]-thymidine incorporation. *P < 0.05 versus respective control; ^P < 0.05 vs. WT. (F) GM-CFU assay from BM isolated from Apoe–/– mice and incubated with increasing concentrations of rHDL. *P < 0.05, ***P < 0.001 vs. control. Data are mean ± SEM.