ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice
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
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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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 5

Infusion of rHDL attenuates monocytosis and neutrophilia by decreasing cellular cholesterol, CBS expression, and HSPC cell cycling in the BM of 4-week WTD-fed Apoe–/– mice.

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Infusion of rHDL attenuates monocytosis and neutrophilia by decreasing c...
After WTD feeding for 4 weeks, Apoe–/– mice were infused with either saline or rHDL (CSL-111; 80 mg/kg), and analysis was performed after 7 days. (A and B) Blood experiments. Data are mean ± SEM (n = 8). (A) Monocytes were assessed via flow cytometry and converted to cells/μl using counts from the complete blood cell analyses. (B) Monocyte proliferation, determined by i.v. injection of EdU 18 hours prior to sacrifice. Proliferation was measured by EdU incorporation into blood monocytes, as determined by flow cytometry. (C–F) BM experiments. Data are mean ± SEM (n = 6–8). (C) HSPCs and downstream progenitors and (D) HSPC subsets, quantified by flow cytometry. (E) HSPCs expressing the CBS. (F) Percent cells in the G2M phase of the cell cycle. (A–F) *P < 0.05, **P < 0.01, ***P < 0.001 vs. WT plus saline; ^P < 0.05, ^^P < 0.01, ^^^P < 0.001 vs. Apoe–/– plus saline.