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

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).

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

  • 2,110
    views
  • 282
    downloads
  • 35
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  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
(2020)
Reprogramming of bone marrow myeloid progenitor cells in patients with severe coronary artery disease
eLife 9:e60939.
https://doi.org/10.7554/eLife.60939

Share this article

https://doi.org/10.7554/eLife.60939

Further reading

    1. Medicine
    Gabriel O Heckerman, Eileen Tzng ... Adrienne Mueller
    Research Article

    Background: Several fields have described low reproducibility of scientific research and poor accessibility in research reporting practices. Although previous reports have investigated accessible reporting practices that lead to reproducible research in other fields, to date, no study has explored the extent of accessible and reproducible research practices in cardiovascular science literature.

    Methods: To study accessibility and reproducibility in cardiovascular research reporting, we screened 639 randomly selected articles published in 2019 in three top cardiovascular science publications: Circulation, the European Heart Journal, and the Journal of the American College of Cardiology (JACC). Of those 639 articles, 393 were empirical research articles. We screened each paper for accessible and reproducible research practices using a set of accessibility criteria including protocol, materials, data, and analysis script availability, as well as accessibility of the publication itself. We also quantified the consistency of open research practices within and across cardiovascular study types and journal formats.

    Results: We identified that fewer than 2% of cardiovascular research publications provide sufficient resources (materials, methods, data, and analysis scripts) to fully reproduce their studies. Of the 639 articles screened, 393 were empirical research studies for which reproducibility could be assessed using our protocol, as opposed to commentaries or reviews. After calculating an accessibility score as a measure of the extent to which an article makes its resources available, we also showed that the level of accessibility varies across study types with a score of 0.08 for Case Studies or Case Series and 0.39 for Clinical Trials (p = 5.500E-5) and across journals (0.19 through 0.34, p = 1.230E-2). We further showed that there are significant differences in which study types share which resources.

    Conclusion: Although the degree to which reproducible reporting practices are present in publications varies significantly across journals and study types, current cardiovascular science reports frequently do not provide sufficient materials, protocols, data, or analysis information to reproduce a study. In the future, having higher standards of accessibility mandated by either journals or funding bodies will help increase the reproducibility of cardiovascular research.

    Funding: Authors Gabriel Heckerman, Arely Campos-Melendez, and Chisomaga Ekwueme were supported by an NIH R25 grant from the National Heart, Lung and Blood Institute (R25HL147666). Eileen Tzng was supported by an AHA Institutional Training Award fellowship (18UFEL33960207).

    1. Cell Biology
    2. Medicine
    Pengbo Chen, Bo Li ... Xinfeng Zheng
    Research Article

    Background:

    It has been reported that loss of PCBP2 led to increased reactive oxygen species (ROS) production and accelerated cell aging. Knockdown of PCBP2 in HCT116 cells leads to significant downregulation of fibroblast growth factor 2 (FGF2). Here, we tried to elucidate the intrinsic factors and potential mechanisms of bone marrow mesenchymal stromal cells (BMSCs) aging from the interactions among PCBP2, ROS, and FGF2.

    Methods:

    Unlabeled quantitative proteomics were performed to show differentially expressed proteins in the replicative senescent human bone marrow mesenchymal stromal cells (RS-hBMSCs). ROS and FGF2 were detected in the loss-and-gain cell function experiments of PCBP2. The functional recovery experiments were performed to verify whether PCBP2 regulates cell function through ROS/FGF2-dependent ways.

    Results:

    PCBP2 expression was significantly lower in P10-hBMSCs. Knocking down the expression of PCBP2 inhibited the proliferation while accentuated the apoptosis and cell arrest of RS-hBMSCs. PCBP2 silence could increase the production of ROS. On the contrary, overexpression of PCBP2 increased the viability of both P3-hBMSCs and P10-hBMSCs significantly. Meanwhile, overexpression of PCBP2 led to significantly reduced expression of FGF2. Overexpression of FGF2 significantly offset the effect of PCBP2 overexpression in P10-hBMSCs, leading to decreased cell proliferation, increased apoptosis, and reduced G0/G1 phase ratio of the cells.

    Conclusions:

    This study initially elucidates that PCBP2 as an intrinsic aging factor regulates the replicative senescence of hBMSCs through the ROS-FGF2 signaling axis.

    Funding:

    This study was supported by the National Natural Science Foundation of China (82172474).