1. Medicine
Download icon

Reprogramming of bone marrow myeloid progenitor cells in patients with severe coronary artery disease

  1. Marlies Noz
  2. Siroon Bekkering
  3. Laszlo Groh
  4. Tim Nielen
  5. Evert Lamfers
  6. Andreas Schlitzer
  7. Saloua El Messaoudi
  8. Niels van Royen
  9. Erik Huys
  10. Frank Preijers
  11. Esther Smeets
  12. Erik Aarntzen
  13. Bowen Zhang
  14. Yang Li
  15. Manita Bremmers
  16. Walter van der Velden
  17. Harry Dolstra
  18. Leo AB Joosten
  19. Marc E Gomes
  20. Mihai G Netea
  21. Niels Peter Riksen  Is a corresponding author
  1. Radboud University Medical Center, Netherlands
  2. Radboud University, Netherlands
  3. Canisius Wilhelmina Hospital, Netherlands
  4. University of Bonn, Germany
  5. Hannover Medical School, Germany
  6. Radboud University Nijmegen Medical Centre, Netherlands
Research Article
  • Cited 3
  • Views 1,099
  • Annotations
Cite this article as: eLife 2020;9:e60939 doi: 10.7554/eLife.60939

Abstract

Atherosclerosis is the major cause of cardiovascular disease (CVD). Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. In patients with atherosclerotic CVD, leukocytes have a hyperinflammatory phenotype. We hypothesize that immune cell reprogramming in these patients occurs at the level of myeloid progenitors. We included 13 patients with coronary artery disease due to severe atherosclerosis and 13 subjects without atherosclerosis in an exploratory study. Cytokine production capacity after ex vivo stimulation of peripheral blood mononuclear cells (MNCs) and bone marrow MNCs was higher in patients with atherosclerosis. In BM-MNCs this was associated with increased glycolysis and oxidative phosphorylation. The BM composition was skewed towards myelopoiesis and transcriptome analysis of HSC/GMP cell populations revealed enrichment of neutrophil- and monocyte-related pathways. These results show that in patients with atherosclerosis, activation of innate immune cells occurs at the level of myeloid progenitors, which adds exciting opportunities for novel treatment strategies.

Data availability

RNA-seq data have been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress)under accession number E-MTAB-9399

Article and author information

Author details

  1. Marlies Noz

    Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Siroon Bekkering

    Internal Medicine, Radboud University, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1149-466X
  3. Laszlo Groh

    Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Tim Nielen

    Cardiology, Canisius Wilhelmina Hospital, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7762-5912
  5. Evert Lamfers

    Cardiology, Canisius Wilhelmina Hospital, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5582-3720
  6. Andreas Schlitzer

    University of Bonn, Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Saloua El Messaoudi

    Cardiology, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Niels van Royen

    Cardiology, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Erik Huys

    Laboratory medicine, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  10. Frank Preijers

    Laboratory medicine, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Esther Smeets

    Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  12. Erik Aarntzen

    Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  13. Bowen Zhang

    Department of Computational Biology for Individualised Infection Medicine, Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Yang Li

    Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  15. Manita Bremmers

    Haematology, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  16. Walter van der Velden

    Haematology, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  17. Harry Dolstra

    Laboratory medicine, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  18. Leo AB Joosten

    Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6166-9830
  19. Marc E Gomes

    Cardiology, Canisius Wilhelmina Hospital, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  20. Mihai G Netea

    Haematology, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  21. Niels Peter Riksen

    Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
    For correspondence
    niels.riksen@radboudumc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9197-8124

Funding

European Unions Horizon 2020 (667837)

  • Leo AB Joosten
  • Mihai G Netea
  • Niels Peter Riksen

Netherlands Organisation for Scientific Research (NWO SPI 94-212)

  • Mihai G Netea

European Commission (833247)

  • Mihai G Netea

ERA-NET (2018T093)

  • Niels Peter Riksen

Netherlands Organisation for Scientic Research (452173113)

  • Siroon Bekkering

Hartstichting (2018T028)

  • Siroon Bekkering

Hartstichting (CVON2018-27)

  • Leo AB Joosten
  • Mihai G Netea
  • Niels Peter Riksen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Informed consent was obtained for all participants.The study protocol was approved by the Institutional Review Board Arnhem/Nijmegen, the Netherlands and registered at the ClinicalTrials.gov (NCT03172507).

Reviewing Editor

  1. Noriaki Emoto, Kobe Pharmaceutical University, Japan

Publication history

  1. Received: July 10, 2020
  2. Accepted: October 27, 2020
  3. Accepted Manuscript published: November 10, 2020 (version 1)
  4. Version of Record published: November 13, 2020 (version 2)

Copyright

© 2020, Noz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,099
    Page views
  • 173
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Medicine
    2. Neuroscience
    Xiao Lv et al.
    Research Article Updated

    The central nervous system regulates activity of peripheral organs through interoception. In our previous study, we have demonstrated that PGE2/EP4 skeleton interception regulate bone homeostasis. Here, we show that ascending skeleton interoceptive signaling downregulates expression of hypothalamic neuropeptide Y (NPY) and induce lipolysis of adipose tissue for osteoblastic bone formation. Specifically, the ascending skeleton interoceptive signaling induces expression of small heterodimer partner-interacting leucine zipper protein (SMILE) in the hypothalamus. SMILE binds to pCREB as a transcriptional heterodimer on Npy promoters to inhibit NPY expression. Knockout of EP4 in sensory nerve increases expression of NPY causing bone catabolism and fat anabolism. Importantly, inhibition of NPY Y1 receptor (Y1R) accelerated oxidation of free fatty acids in osteoblasts and rescued bone loss in AvilCre:Ptger4fl/fl mice. Thus, downregulation of hypothalamic NPY expression lipolyzes free fatty acids for anabolic bone formation through a neuroendocrine descending interoceptive regulation.

    1. Medicine
    Abudupataer Mieradilijiang et al.
    Research Article

    Background: Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified.

    Methods: A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta smooth muscle-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs).

    Results: Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients.

    Conclusions: The aorta smooth muscle-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta smooth muscle-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA.

    Funding: National Key R&D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.