ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice
Open accessAbstract
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 proteoglycanbound 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.
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Macrophage apoE effects manifest as modulation of the macrophage inflammatory response in the atheroma.
“Atherogenesis is infl uenced by macrophage expression of apoE ( 11 ), the effects of which manifest as: 1 ) secretion into the circulation and association with lipoproteins to mediate their hepatic uptake ( 3, 6 ); and 2 ) modulation of the macrophage infl ammatory response in the atheroma ( 16,17 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [17]
The Discussion reports that Apoe-deficient monocytes were slightly activated and suggests they may be primed to respond to signals within lesions. It does not establish that macrophage apoE modulates the inflammatory response of macrophages in the atheroma; the paper’s demonstrated mechanism centers on stem-cell proliferation and monocyte accumulation. (LLM, conf=0.78)
Experimental — accuracy not yet measuredApoE's effect appears to occur mainly in a cell-autonomous manner by regulating cellular cholesterol content, which critically regulates the level of membrane-associated signaling complexes that are essential for triggering cell proliferation.
“ApoE’s effect appears to occur mainly in a cell-autonomous manner by regulating cellular cholesterol content, which critically regulates the level of membrane-associated signaling complexes that are essential for triggering cell proliferation (Murphy et al., 2011).”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Murphy et al., 2011
The ability of apoE to inhibit cell proliferation has been reported in other cell types, such as hippocampal neural stem/progenitor cells and hematopoietic cells.
“The ability of apoE to inhibit cell proliferation has also been reported in other cell types, such as hippocampal neural stem/progenitor cells (NSC/NPC) (Yang et al., 2011) and hematopoietic cells (Murphy et al., 2011).”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Murphy et al., 2011
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- Authors
- Murphy, A. J., Akhtari, M., Tolani, S., Pagler, T., Bijl, N., Kuo, C.-L., Wang, M., Sanson, M., Abramowicz, S., Welch, C., Bochem, A. E., Kuivenhoven, J. A., Yvan-Charvet, L., & Tall, A. R.
- Affiliations
- Columbia University Irving Medical Center (US)
- Columbia University (US)
- New York University (US)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Murphy, Andrew J.
- Venue
- Journal of Clinical Investigation
- Published
- 2011-10-03
- Volume
- 121
- Issue
- 10
- Pages
- 4138-4149
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3195472
- OpenAlex
- W2145899814
- Cited by
- 521
- References
- 3
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 26 · 2023: 33 · 2022: 41 · 2021: 40 · 2020: 48 · 2019: 41 · 2018: 46 · 2017: 21 · 2016: 44 · 2015: 21 · 2014: 44 · 2013: 37 · 2012: 25
- FWCI
- 36.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion, other-oa)
- Pure Amsterdam UMC (publishedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- American Heart Association (SDG2160053)
- Sarnoff Cardiovascular Research Foundation
- National Institutes of Health (HL107653)
- U.S. Public Health Service (54591)
- National Heart, Lung, and Blood Institute (R01HL084312, HL-084312, HL107653, R01HL107653)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- apolipoprotein E, hematopoietic stem and progenitor cells, monocytosis, neutrophilia, atherosclerosis, cholesterol efflux, ABCA1, ABCG1, apolipoprotein A-I, leukocytosis, monocyte accumulation, HDL cholesterol, liver X receptor, Western diet, bone marrow transplantation
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 1, Animals, Apolipoproteins E, Cholesterol, Disease Models, Animal, Hematopoietic Stem Cells, Humans, Leukocytosis, Lipoproteins, Mice, Inbred C57BL, Models, Cardiovascular, Monocytes, Proteoglycans, Receptors, LDL, Apolipoprotein A-I, Mice, Knockout, ATP-Binding Cassette Transporters, Cell Proliferation, Atherosclerosis, Mice, ATP Binding Cassette Transporter 1
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