Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Article has an altmetric score of 3

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

  • Text
  • PDF
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

×

Figure 1

Feeding Ldlr–/– and Apoe–/– mice a WTD induces leukocytosis, expansion of HSPCs, increased GM-CFUs, and proliferation of BM myeloid cells.

Options: View larger image (or click on image) Download as PowerPoint
Feeding Ldlr–/– and Apoe–/– mice a WTD induces leukocytosis, expansion o...
8-week-old mice were fed a WTD for the indicated time periods. (A) Plasma cholesterol levels. (B and C) Monocytes and neutrophils were analyzed by flow cytometry and expressed as a percentage of CD45+ leukocytes. (D and E) The HSPC population was assessed by flow cytometry and is expressed as a percentage of total BM cells. (F) GM-CFU assays from isolated BM. (G) BM proliferation was evaluated by [3H]-thymidine incorporation into DNA. (A–G) *P < 0.05 vs. 0 weeks; ^P < 0.05 vs. Ldlr–/– at the respective time point. Data are mean ± SEM, n = 6–8. (H) WT, Apoa1–/–, Apoe–/–, and Apoa1–/–Apoe–/– mice were fed a chow diet until 20 weeks of age. The population of blood monocytes was identified by flow cytometry. *P < 0.05 vs. WT. Data are mean ± SEM, n = 5–8.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Referenced in 2 patents
264 readers on Mendeley
See more details