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

Marlies P Noz, Siroon Bekkering, Laszlo Groh, Tim Mj Nielen, Evert Jp Lamfers, Andreas Schlitzer, Saloua El Messaoudi, Niels van Royen, Erik Hjpg Huys, Frank Wmb Preijers, Esther Mm Smeets, Erik Hjg Aarntzen, Bowen Zhang, Yang Li, Manita Ej Bremmers, Walter Jfm van der Velden, Harry Dolstra, Leo Ab Joosten, Marc E Gomes, Mihai G Netea, Niels P Riksen, Marlies P Noz, Siroon Bekkering, Laszlo Groh, Tim Mj Nielen, Evert Jp Lamfers, Andreas Schlitzer, Saloua El Messaoudi, Niels van Royen, Erik Hjpg Huys, Frank Wmb Preijers, Esther Mm Smeets, Erik Hjg Aarntzen, Bowen Zhang, Yang Li, Manita Ej Bremmers, Walter Jfm van der Velden, Harry Dolstra, Leo Ab Joosten, Marc E Gomes, Mihai G Netea, Niels P Riksen

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.

Trial registration: ClinicalTrials.gov NCT03172507.

Keywords: atherosclerosis; bone marrow; cardiovascular diseases; haematopoietic stem; human; immune memory; medicine; progenitor cells; trained immunity.

Conflict of interest statement

MN, SB, LG, TN, EL, AS, SE, Nv, EH, FP, ES, EA, BZ, YL, MB, Wv, HD, LJ, MG, MN, NR No competing interests declared

© 2020, Noz et al.

Figures

Figure 1.. Cytokine production capacity of circulating…
Figure 1.. Cytokine production capacity of circulating PBMCs.
(A) Cytokine production capacity of circulating PBMCs after LPS stimulation in control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). Geometric mean with 95% CI. (B) Table of cytokine/chemokine production (x-axis) after stimulation with LPS or P3C (y-axis) of PBMCs showing statistical differences between groups. The p-values are corrected for age and BMI with ANCOVA. Outliers were removed with an SD of >2.5 of Z-scores. * indicates p<0.05, **: p<0.01.
Figure 2.. Progenitor cell populations in the…
Figure 2.. Progenitor cell populations in the bone marrow compartment (A–G) and in the circulation (H and I).
Control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). HSC and MPP cell populations were combined as the CD90 expression marker was not available for n = 6 in each study group. Geometric mean with 95% CI. The p-values are corrected for age and BMI with ANCOVA. * indicates p

Figure 2—figure supplement 1.. Gating strategy of…

Figure 2—figure supplement 1.. Gating strategy of hematopoietic stem and progenitor cells in the bone…

Figure 2—figure supplement 1.. Gating strategy of hematopoietic stem and progenitor cells in the bone marrow.
HSPCs were defined as CD45+CD34+CD38dim cells, after exclusion of dead cells and doublets. Next, the lymphoid lineage was excluded in CD19-CD117+ cells. In CD45RAdimCD38+ cells, CMP, GMP, MEP, and R1-3 progenitor populations were identified using CD123 and CD45RA expression, see Table for details. CD90 expression in CD38-CD45RA- cells determined MPP and HSC populations.

Figure 3.. Cytokine production capacity of bone…

Figure 3.. Cytokine production capacity of bone marrow MNCs.

( A ) Cytokine production capacity…

Figure 3.. Cytokine production capacity of bone marrow MNCs.
(A) Cytokine production capacity of BM-MNCs after LPS stimulation in control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). Geometric mean with 95% CI. (B) Table of cytokine/chemokine production (x-axis) after stimulation with LPS or P3C (y-axis) of BM-MNCs showing statistical differences between groups. The p-values are corrected for age and BMI with ANCOVA. Outliers were removed with an SD of >2.5 of Z-scores. * indicates p<0.05, **: p<0.01.

Figure 4.. Metabolism of BM-MNCs assessed with…

Figure 4.. Metabolism of BM-MNCs assessed with Seahorse respirometry in unstimulated condition and 2 hours…

Figure 4.. Metabolism of BM-MNCs assessed with Seahorse respirometry in unstimulated condition and 2 hours after IFN-γ+LPS stimulation.
(A, B) Oxygen consumption and extracellular acidification rates over time using treatment with Oligomycin, FCCP, and Rotenone/Antimycin A. (C, D) Bar graphs of control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). Geometric mean with 95% CI. The p-values are corrected for age and BMI with ANCOVA. * indicates p<0.05, **: p<0.01. IFN-γ+LPS: 2 hr IFN-γ and LPS stimulation.

Figure 5.. Proliferation capacity of bone marrow…

Figure 5.. Proliferation capacity of bone marrow MNCs.

Counted colonies per 10 3 cultured BM-MNCs…

Figure 5.. Proliferation capacity of bone marrow MNCs.
Counted colonies per 103 cultured BM-MNCs of control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). Geometric mean with 95% CI. The p-values are corrected for age and BMI with ANCOVA. BFU-E indicates erythroid progenitor population, CFU-GEMM: myeloid progenitor population, CFU-GM: granulocyte-macrophage progenitor population.

Figure 6.. Transcriptome analyses of HSC, MPP,…

Figure 6.. Transcriptome analyses of HSC, MPP, and GMP populations.

Control individuals (n = 10)…

Figure 6.. Transcriptome analyses of HSC, MPP, and GMP populations.
Control individuals (n = 10) versus individuals with CAD (n = 10) for each cell population. (A) Principle component analysis (PCA) based on differentially expressed (DE) genes of the HSC population; (B) Volcano plot showing differential expressed genes between patients with CAD and individuals without atherosclerosis, controlled for age, in a combined analysis of HSC, MPP, and GMP population. Genes with an FDR <0.1 are named; (C) Gene ontology enrichment analysis of DE genes from HSCs, MPPs, and GMPs, depicting the FDR and enrichment ratio.

Figure 6—figure supplement 1.. Transcriptome of HSC,…

Figure 6—figure supplement 1.. Transcriptome of HSC, MPP, and GMP populations.

( A ) PCA…

Figure 6—figure supplement 1.. Transcriptome of HSC, MPP, and GMP populations.
(A) PCA analysis based on DE genes of the GMP and MPP cell population; (B) Volcano plot showing differential expressed genes between CAD patients and controls, controlled for age, in the HSC, MPP, and GMP cell populations. Genes with an FDR <0.1 are called out.

Figure 6—figure supplement 2.. Combined heatmap showing…

Figure 6—figure supplement 2.. Combined heatmap showing the top 50 DE genes for the HSC,…

Figure 6—figure supplement 2.. Combined heatmap showing the top 50 DE genes for the HSC, MPP, and GMP cell populations in the patients and the control subjects.
Genes with an FDR 

Figure 6—figure supplement 3.. Separated heatmap showing…

Figure 6—figure supplement 3.. Separated heatmap showing the top 50 DE genes for each of…

Figure 6—figure supplement 3.. Separated heatmap showing the top 50 DE genes for each of the HSC, MPP, and GMP cell populations in the patients and the control subjects.
Genes with an FDR 

Figure 7.. Vascular wall inflammation and hematopoietic…

Figure 7.. Vascular wall inflammation and hematopoietic tissue activation on [ 18 F]FDG PET/CT scan.

Standard uptake…

Figure 7.. Vascular wall inflammation and hematopoietic tissue activation on [18F]FDG PET/CT scan.
Standard uptake value of each region in control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). Geometric mean with 95% CI. The p-values are corrected for age and BMI with ANCOVA.* indicates p

Figure 7—figure supplement 1.. Splenic activity correlates…

Figure 7—figure supplement 1.. Splenic activity correlates with progenitor cells and circulating immune cells.

Linear…

Figure 7—figure supplement 1.. Splenic activity correlates with progenitor cells and circulating immune cells.
Linear regression with 95% CI (n = 26). Spearman correlation coefficient (rs). * indicates p<0.05, **: p<0.01. HSPCs: hematopoietic stem and progenitor cells, GMP: granulocyte macrophage progenitor cells, WBC: white blood cells.

Author response image 1.

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All figures (13)
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Cited by
References
    1. Arts RJW, Moorlag S, Novakovic B, Li Y, Wang SY, Oosting M, Kumar V, Xavier RJ, Wijmenga C, Joosten LAB, Reusken C, Benn CS, Aaby P, Koopmans MP, Stunnenberg HG, van Crevel R, Netea MG. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host & Microbe. 2018;23:89–100. doi: 10.1016/j.chom.2017.12.010. - DOI - PubMed
    1. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G. Gene ontology: tool for the unification of biology the gene ontology consortium. Nature Genetics. 2000;25:25–29. doi: 10.1038/75556. - DOI - PMC - PubMed
    1. Bekkering S, van den Munckhof I, Nielen T, Lamfers E, Dinarello C, Rutten J, de Graaf J, Joosten LA, Netea MG, Gomes ME, Riksen NP. Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo. Atherosclerosis. 2016;254:228–236. doi: 10.1016/j.atherosclerosis.2016.10.019. - DOI - PubMed
    1. Bekkering S, Stiekema LCA, Bernelot Moens S, Verweij SL, Novakovic B, Prange K, Versloot M, Roeters van Lennep JE, Stunnenberg H, de Winther M, Stroes ESG, Joosten LAB, Netea MG, Riksen NP. Treatment with statins does not revert trained immunity in patients with familial hypercholesterolemia. Cell Metabolism. 2019;30:1–2. doi: 10.1016/j.cmet.2019.05.014. - DOI - PubMed
    1. Bucerius J, Hyafil F, Verberne HJ, Slart RH, Lindner O, Sciagra R, Agostini D, Übleis C, Gimelli A, Hacker M, Cardiovascular Committee of the European Association of Nuclear Medicine (EANM) Position paper of the cardiovascular committee of the european association of nuclear medicine (EANM) on PET imaging of atherosclerosis. European Journal of Nuclear Medicine and Molecular Imaging. 2016;43:780–792. doi: 10.1007/s00259-015-3259-3. - DOI - PMC - PubMed
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Figure 2—figure supplement 1.. Gating strategy of…
Figure 2—figure supplement 1.. Gating strategy of hematopoietic stem and progenitor cells in the bone marrow.
HSPCs were defined as CD45+CD34+CD38dim cells, after exclusion of dead cells and doublets. Next, the lymphoid lineage was excluded in CD19-CD117+ cells. In CD45RAdimCD38+ cells, CMP, GMP, MEP, and R1-3 progenitor populations were identified using CD123 and CD45RA expression, see Table for details. CD90 expression in CD38-CD45RA- cells determined MPP and HSC populations.
Figure 3.. Cytokine production capacity of bone…
Figure 3.. Cytokine production capacity of bone marrow MNCs.
(A) Cytokine production capacity of BM-MNCs after LPS stimulation in control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). Geometric mean with 95% CI. (B) Table of cytokine/chemokine production (x-axis) after stimulation with LPS or P3C (y-axis) of BM-MNCs showing statistical differences between groups. The p-values are corrected for age and BMI with ANCOVA. Outliers were removed with an SD of >2.5 of Z-scores. * indicates p<0.05, **: p<0.01.
Figure 4.. Metabolism of BM-MNCs assessed with…
Figure 4.. Metabolism of BM-MNCs assessed with Seahorse respirometry in unstimulated condition and 2 hours after IFN-γ+LPS stimulation.
(A, B) Oxygen consumption and extracellular acidification rates over time using treatment with Oligomycin, FCCP, and Rotenone/Antimycin A. (C, D) Bar graphs of control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). Geometric mean with 95% CI. The p-values are corrected for age and BMI with ANCOVA. * indicates p<0.05, **: p<0.01. IFN-γ+LPS: 2 hr IFN-γ and LPS stimulation.
Figure 5.. Proliferation capacity of bone marrow…
Figure 5.. Proliferation capacity of bone marrow MNCs.
Counted colonies per 103 cultured BM-MNCs of control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). Geometric mean with 95% CI. The p-values are corrected for age and BMI with ANCOVA. BFU-E indicates erythroid progenitor population, CFU-GEMM: myeloid progenitor population, CFU-GM: granulocyte-macrophage progenitor population.
Figure 6.. Transcriptome analyses of HSC, MPP,…
Figure 6.. Transcriptome analyses of HSC, MPP, and GMP populations.
Control individuals (n = 10) versus individuals with CAD (n = 10) for each cell population. (A) Principle component analysis (PCA) based on differentially expressed (DE) genes of the HSC population; (B) Volcano plot showing differential expressed genes between patients with CAD and individuals without atherosclerosis, controlled for age, in a combined analysis of HSC, MPP, and GMP population. Genes with an FDR <0.1 are named; (C) Gene ontology enrichment analysis of DE genes from HSCs, MPPs, and GMPs, depicting the FDR and enrichment ratio.
Figure 6—figure supplement 1.. Transcriptome of HSC,…
Figure 6—figure supplement 1.. Transcriptome of HSC, MPP, and GMP populations.
(A) PCA analysis based on DE genes of the GMP and MPP cell population; (B) Volcano plot showing differential expressed genes between CAD patients and controls, controlled for age, in the HSC, MPP, and GMP cell populations. Genes with an FDR <0.1 are called out.
Figure 6—figure supplement 2.. Combined heatmap showing…
Figure 6—figure supplement 2.. Combined heatmap showing the top 50 DE genes for the HSC, MPP, and GMP cell populations in the patients and the control subjects.
Genes with an FDR 

Figure 6—figure supplement 3.. Separated heatmap showing…

Figure 6—figure supplement 3.. Separated heatmap showing the top 50 DE genes for each of…

Figure 6—figure supplement 3.. Separated heatmap showing the top 50 DE genes for each of the HSC, MPP, and GMP cell populations in the patients and the control subjects.
Genes with an FDR 

Figure 7.. Vascular wall inflammation and hematopoietic…

Figure 7.. Vascular wall inflammation and hematopoietic tissue activation on [ 18 F]FDG PET/CT scan.

Standard uptake…

Figure 7.. Vascular wall inflammation and hematopoietic tissue activation on [18F]FDG PET/CT scan.
Standard uptake value of each region in control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). Geometric mean with 95% CI. The p-values are corrected for age and BMI with ANCOVA.* indicates p

Figure 7—figure supplement 1.. Splenic activity correlates…

Figure 7—figure supplement 1.. Splenic activity correlates with progenitor cells and circulating immune cells.

Linear…

Figure 7—figure supplement 1.. Splenic activity correlates with progenitor cells and circulating immune cells.
Linear regression with 95% CI (n = 26). Spearman correlation coefficient (rs). * indicates p<0.05, **: p<0.01. HSPCs: hematopoietic stem and progenitor cells, GMP: granulocyte macrophage progenitor cells, WBC: white blood cells.

Author response image 1.

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Author response image 1.
All figures (13)
Similar articles
Cited by
References
    1. Arts RJW, Moorlag S, Novakovic B, Li Y, Wang SY, Oosting M, Kumar V, Xavier RJ, Wijmenga C, Joosten LAB, Reusken C, Benn CS, Aaby P, Koopmans MP, Stunnenberg HG, van Crevel R, Netea MG. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host & Microbe. 2018;23:89–100. doi: 10.1016/j.chom.2017.12.010. - DOI - PubMed
    1. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G. Gene ontology: tool for the unification of biology the gene ontology consortium. Nature Genetics. 2000;25:25–29. doi: 10.1038/75556. - DOI - PMC - PubMed
    1. Bekkering S, van den Munckhof I, Nielen T, Lamfers E, Dinarello C, Rutten J, de Graaf J, Joosten LA, Netea MG, Gomes ME, Riksen NP. Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo. Atherosclerosis. 2016;254:228–236. doi: 10.1016/j.atherosclerosis.2016.10.019. - DOI - PubMed
    1. Bekkering S, Stiekema LCA, Bernelot Moens S, Verweij SL, Novakovic B, Prange K, Versloot M, Roeters van Lennep JE, Stunnenberg H, de Winther M, Stroes ESG, Joosten LAB, Netea MG, Riksen NP. Treatment with statins does not revert trained immunity in patients with familial hypercholesterolemia. Cell Metabolism. 2019;30:1–2. doi: 10.1016/j.cmet.2019.05.014. - DOI - PubMed
    1. Bucerius J, Hyafil F, Verberne HJ, Slart RH, Lindner O, Sciagra R, Agostini D, Übleis C, Gimelli A, Hacker M, Cardiovascular Committee of the European Association of Nuclear Medicine (EANM) Position paper of the cardiovascular committee of the european association of nuclear medicine (EANM) on PET imaging of atherosclerosis. European Journal of Nuclear Medicine and Molecular Imaging. 2016;43:780–792. doi: 10.1007/s00259-015-3259-3. - DOI - PMC - PubMed
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Figure 6—figure supplement 3.. Separated heatmap showing…
Figure 6—figure supplement 3.. Separated heatmap showing the top 50 DE genes for each of the HSC, MPP, and GMP cell populations in the patients and the control subjects.
Genes with an FDR 

Figure 7.. Vascular wall inflammation and hematopoietic…

Figure 7.. Vascular wall inflammation and hematopoietic tissue activation on [ 18 F]FDG PET/CT scan.

Standard uptake…

Figure 7.. Vascular wall inflammation and hematopoietic tissue activation on [18F]FDG PET/CT scan.
Standard uptake value of each region in control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). Geometric mean with 95% CI. The p-values are corrected for age and BMI with ANCOVA.* indicates p

Figure 7—figure supplement 1.. Splenic activity correlates…

Figure 7—figure supplement 1.. Splenic activity correlates with progenitor cells and circulating immune cells.

Linear…

Figure 7—figure supplement 1.. Splenic activity correlates with progenitor cells and circulating immune cells.
Linear regression with 95% CI (n = 26). Spearman correlation coefficient (rs). * indicates p<0.05, **: p<0.01. HSPCs: hematopoietic stem and progenitor cells, GMP: granulocyte macrophage progenitor cells, WBC: white blood cells.

Author response image 1.

Author response image 1.

Author response image 1.
All figures (13)
Similar articles
Cited by
References
    1. Arts RJW, Moorlag S, Novakovic B, Li Y, Wang SY, Oosting M, Kumar V, Xavier RJ, Wijmenga C, Joosten LAB, Reusken C, Benn CS, Aaby P, Koopmans MP, Stunnenberg HG, van Crevel R, Netea MG. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host & Microbe. 2018;23:89–100. doi: 10.1016/j.chom.2017.12.010. - DOI - PubMed
    1. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G. Gene ontology: tool for the unification of biology the gene ontology consortium. Nature Genetics. 2000;25:25–29. doi: 10.1038/75556. - DOI - PMC - PubMed
    1. Bekkering S, van den Munckhof I, Nielen T, Lamfers E, Dinarello C, Rutten J, de Graaf J, Joosten LA, Netea MG, Gomes ME, Riksen NP. Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo. Atherosclerosis. 2016;254:228–236. doi: 10.1016/j.atherosclerosis.2016.10.019. - DOI - PubMed
    1. Bekkering S, Stiekema LCA, Bernelot Moens S, Verweij SL, Novakovic B, Prange K, Versloot M, Roeters van Lennep JE, Stunnenberg H, de Winther M, Stroes ESG, Joosten LAB, Netea MG, Riksen NP. Treatment with statins does not revert trained immunity in patients with familial hypercholesterolemia. Cell Metabolism. 2019;30:1–2. doi: 10.1016/j.cmet.2019.05.014. - DOI - PubMed
    1. Bucerius J, Hyafil F, Verberne HJ, Slart RH, Lindner O, Sciagra R, Agostini D, Übleis C, Gimelli A, Hacker M, Cardiovascular Committee of the European Association of Nuclear Medicine (EANM) Position paper of the cardiovascular committee of the european association of nuclear medicine (EANM) on PET imaging of atherosclerosis. European Journal of Nuclear Medicine and Molecular Imaging. 2016;43:780–792. doi: 10.1007/s00259-015-3259-3. - DOI - PMC - PubMed
Show all 45 references
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Related information
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 7.. Vascular wall inflammation and hematopoietic…
Figure 7.. Vascular wall inflammation and hematopoietic tissue activation on [18F]FDG PET/CT scan.
Standard uptake value of each region in control individuals (white bars, n = 13) and individuals with CAD (gray bars, n = 13). Geometric mean with 95% CI. The p-values are corrected for age and BMI with ANCOVA.* indicates p

Figure 7—figure supplement 1.. Splenic activity correlates…

Figure 7—figure supplement 1.. Splenic activity correlates with progenitor cells and circulating immune cells.

Linear…

Figure 7—figure supplement 1.. Splenic activity correlates with progenitor cells and circulating immune cells.
Linear regression with 95% CI (n = 26). Spearman correlation coefficient (rs). * indicates p<0.05, **: p<0.01. HSPCs: hematopoietic stem and progenitor cells, GMP: granulocyte macrophage progenitor cells, WBC: white blood cells.

Author response image 1.

Author response image 1.

Author response image 1.
All figures (13)
Figure 7—figure supplement 1.. Splenic activity correlates…
Figure 7—figure supplement 1.. Splenic activity correlates with progenitor cells and circulating immune cells.
Linear regression with 95% CI (n = 26). Spearman correlation coefficient (rs). * indicates p<0.05, **: p<0.01. HSPCs: hematopoietic stem and progenitor cells, GMP: granulocyte macrophage progenitor cells, WBC: white blood cells.
Author response image 1.
Author response image 1.

References

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