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Bone marrow adipocytes fuel emergency hematopoiesis after myocardial infarction

Nature Cardiovascular Research volume 2, pages 1277–1290 (2023)Cite this article

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Abstract

After myocardial infarction (MI), emergency hematopoiesis produces inflammatory myeloid cells that accelerate atherosclerosis and promote heart failure. Because the balance between glycolysis and mitochondrial metabolism regulates hematopoietic stem cell homeostasis, metabolic cues may influence emergency myelopoiesis. Here we show, in humans and female mice, that hematopoietic progenitor cells increase fatty acid metabolism after MI. Blockade of fatty acid oxidation by deleting carnitine palmitoyltransferase (Cpt1a) in hematopoietic cells of Vav1Cre/+Cpt1afl/fl mice limited hematopoietic progenitor proliferation and myeloid cell expansion after MI. We also observed reduced bone marrow adiposity in humans, pigs and mice after MI. Inhibiting lipolysis in adipocytes using AdipoqCreERT2Atglfl/fl mice or local depletion of bone marrow adipocytes in AdipoqCreERT2iDTR mice also curbed emergency hematopoiesis. Furthermore, systemic and regional sympathectomy prevented bone marrow adipocyte shrinkage after MI. These data establish a critical role for fatty acid metabolism in post-MI emergency hematopoiesis.

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Fig. 1: MI enhances fatty acid metabolism in HSPCs.
Fig. 2: HSPCs display increased fatty acid content in response to MI.
Fig. 3: Fatty acid oxidation is required for emergency hematopoiesis after MI.
Fig. 4: MI reduces bone marrow adiposity.
Fig. 5: Fatty acids from bone marrow adipocytes are required for increased myelopoiesis after MI.
Fig. 6: Local depletion of bone marrow adipocytes leads to reduced emergency hematopoiesis.
Fig. 7: Sympathetic nerve fibers regulate the release of fatty acids from bone marrow adipocytes in response to MI.

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Data availability

The data were deposited in the National Center for Biotechnology Information’s Gene Expression Omnibus (GEO) and are accessible through GEO series accession number GSE169267. The DepMap public database was used for Extended Data Fig. 2c.

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Acknowledgements

This work was funded, in part, by the National Institutes of Health (NIH) (HL142494, HL139598, HL125428, NS108419 and T32HL076136), the Massachusetts General Hospital (MGH) Research Scholar Program, the Deutsche Forschungsgemeinschaft (RO5071/1-1 to D.R. and SCHL 2221/1-1 to M.J.S.), the Italian Ministry of Health ‘Ricerca Corrente’ (to D.C.) and Siemens Healthineers. J.G. was supported by the German Centre for Cardiovascular Research (DZHK) and the German Research Foundation (DFG, SFB 1470 subproject A4, GR 5261/1-1). The authors thank the MGH Mouse Imaging Program for assistance with imaging, the Center for Skeletal Research Core (NIH P30 AR066261) for histological processing and micro-CT imaging, the Harvard Stem Cell Institute–Center for Regenerative Medicine Flow Cytometry Core for assistance with flow sorting, the Harvard Center for Mass Spectrometry for metabolomics and K. Joyes (Center for Systems Biology) for editing the manuscript. We acknowledge BioRender (BE261P1NT4) for the cartoon component.

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Author notes

  1. These authors contributed equally: Shuang Zhang, Alexandre Paccalet.

Authors and Affiliations

  1. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Shuang Zhang, Alexandre Paccalet, David Rohde, Sebastian Cremer, Maarten Hulsmans, I-Hsiu Lee, Kyle Mentkowski, Jana Grune, Maximilian J. Schloss, Lisa Honold, Yoshiko Iwamoto, Michael A. Moskowitz, Kamila Naxerova & Matthias Nahrendorf

  2. Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Shuang Zhang, Alexandre Paccalet, David Rohde, Sebastian Cremer, Maarten Hulsmans, I-Hsiu Lee, Kyle Mentkowski, Jana Grune, Maximilian J. Schloss, Lisa Honold, Yi Zheng, Miriam A. Bredella, Colleen Buckless, Brian Ghoshhajra, Vikas Thondapu, Michael A. Moskowitz, Kamila Naxerova & Matthias Nahrendorf

  3. Department of Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Anja M. van der Laan & Jan J. Piek

  4. Department of Pathology and Cardiac Surgery, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VU Medical Center, Amsterdam, The Netherlands

    Hans W. M. Niessen

  5. Department of AngioCardioNeurology and Translational Medicine, I.R.C.C.S. INM Neuromed, Pozzilli, Italy

    Fabio Pallante, Raimondo Carnevale, Sara Perrotta & Daniela Carnevale

  6. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy

    Daniela Carnevale

  7. Institut del Cor Germans Trias i Pujol, Barcelona, Spain

    Oriol Iborra-Egea, Christian Muñoz-Guijosa, Carolina Galvez-Monton & Antoni Bayes-Genis

  8. Harvard Center for Mass Spectrometry, Harvard University, Cambridge, MA, USA

    Charles Vidoudez & Sunia A. Trauger

  9. Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA

    David T. Scadden

  10. Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Filip K. Swirski

  11. Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Matthias Nahrendorf

  12. Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany

    Matthias Nahrendorf

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  1. Shuang Zhang
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Contributions

S.Z., D.R., S.C., M.H., I.-H. L., J.G., L.H., Y.I., M.J.S., K.M., A.P., Y.Z., F.P., R.C., S.P., M.A.B., C.B., B.G., V.T., A.M.v.d.L., J.J.P., H.W.M.N. and D.C. designed, performed and analyzed experiments. I.-H.L. and K.N. analyzed and processed RNA sequencing data. S.Z., D.R., S.C., M.H., A.P., M.A.B., M.A.M., D.C., D.S., F.K.S., K.N. and M.N. discussed results and strategy. O.I.-E., C.G.-M. and A.B.-G. collected and provided human and swine bone marrow specimens. C.V. and S.A.T. performed and analyzed mass spectrometry experiments. S.Z., A.P., D.R. and M.N. wrote the manuscript, with input from all authors.

Corresponding author

Correspondence to Matthias Nahrendorf.

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Competing interests

M.N. has been a paid consultant or received research support from Takeda, Novartis, GlaxoSmithKline, Medtronic, Verseaux, Sigilon, Alnylam, IFM Therapeutics, Pfizer, Bitteroot and Molecular Imaging. All other authors declare no conflicts of interest, financial or otherwise.

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Extended data

Extended Data Fig. 1 Glucose uptake capacity of bone marrow GMP post MI and baseline phenotype in Vav1iCre+Cpt1afl/fl mice.

a, Representative flow cytometry plots, showing the gating strategy on GMP. b, Flow histograms and c, statistical analysis of 2-NBD glucose fluorescence in GMP isolated from naive controls and mice on day 1 and 3 post MI. Data are displayed as mean ± s.e.m. (n = 8 per time, Brown-Forsythe and Welsh Anova with Dunnett’s T3 multiple comparison, two independent experiments) d, Experimental design. e, Gating strategy for blood leukocytes. f, Quantification of blood leukocytes in naive Cpt1afl/fl controls and Vav1iCre+Cpt1Afl/fl mice (n = 8 Cpt1afl/fl, n = 7 Vav1Cre+Cpt1afl/fl, two-tailed Welch’s t test, two independent experiments). g, Quantification of HSPC numbers and proliferation in naive Cpt1afl/fl controls and Vav1iCre+Cpt1afl/fl mice (n = 8 Cpt1afl/fl, n = 8 Vav1iCre+Cpt1afl/fl, two-tailed Welch’s t test, two independent experiments). h, Representative flow cytometry plot, gating strategy on GMP and histogram for puromycin quantification. i, GMP glucose dependency and FAO capacity (n = 5 Cpt1afl/fl n = 6 Vav1iCre+Cpt1afl/fl, two-tailed unpaired t-test, two independent experiments). Data are displayed as mean ± SEM.

Source data

Extended Data Fig. 2 Hematopoietic Cpt1a deficiency reduces hematopoiesis.

a, Quantification of blood leukocytes in Cpt1afl/fl controls and Vav1iCre+Cpt1afl/fl mice on day 3 after MI (n = 6 Cpt1afl/fl, n = 7 Vav1iCre+Cpt1afl/fl, two-tailed Welch’s t test, three independent experiments). b, Bone marrow SLAM-LSK numbers and proliferation and leukocyte numbers in Cpt1afl/fl controls and Vav1iCre+Cpt1afl/fl mice on day 3 after MI (n = 6 Cpt1afl/fl, n = 8 Vav1iCre+Cpt1afl/fl, two-tailed Welch’s t test, three independent experiments). Data are displayed as mean ± SEM. c, Gene essentiality (Chronos) scores for CPT1A (red curve) and F13B (blue, a control gene expressed in hematopoietic cells).

Source data

Extended Data Fig. 3 Deletion of Cpt1a from HSPC and their progeny does not change post-MI outcomes 3 weeks later.

a, Experimental Outline. b, Left ventricular morphology and function measured by cardiac magnetic resonance imaging (MRI) 3 weeks after coronary ligation in Cpt1afl/fl controls and Vav1iCre+Cpt1afl/fl mice (n = 7 and 13, two-tailed unpaired t-tests, three independent experiments). Data are displayed as mean ± s.e.m.

Source data

Extended Data Fig. 4 Expanded proliferation of hematopoietic stem and progenitor cells in the adipocyte-rich metaphysis after myocardial infarction.

a, Quantification of adipocytes in femur diaphysis versus metaphysis (n = 9 mice, two-tailed paired t test, three independent experiments). Data are displayed as mean ± SEM.b, Immunofluorescent staining of adipocytes in femur. c, Flow plots of BrdU incorporation into GMP, LSK and SLAM-LSK in the femur diaphysis versus metaphysis in mice on day 3 after MI. d, Quantification of GMP, LSK and SLAM-LSK proliferation in femur diaphysis versus metaphysis (n = 10 mice for diaphysis, n = 10 mice for metaphysis, two-tailed Welch’s t test, three independent experiments). Data are displayed as mean ± SEM e, Quantification of adipocytes number and size on indicated days after surgery (n = 5-6 per time, One-way ANOVA with Tukey’s multiple comparison tests, two independent experiments) Data are displayed as mean ± SEM f, Hematoxylin and eosin (H&E) stain for subcutaneous adipocytes in control mice and on day 3 after MI. g, Quantification of subcutaneous adipocyte size in control mice and on day 3 after MI (n = 20 fields of view for 3control mice, n = 20 fields of view for3 mice with MI, two-tailed Welch’s t test). Data are displayed as mean ± SEM h, H&E stain for visceral adipocytes in control mice and on day 3 after MI. h, Quantification of visceral adipocyte size in control mice and on day 3 after MI (n = 20 fields of view for 3 control mice, n = 20 fields of view for 3 mice with MI, two-tailed Welch’s t test). Data are displayed as mean ± SEM. j, Percentage of counted labeled cells in the respective distance range of a bone marrow adipocyte in control and MI mice (77 cells counted in control and 61 in MI mice, three independent experiments).

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Extended Data Fig. 5 Baseline hematopoiesis and leukocyte profile in AdipoqCreERT2Atglfl/fl mice.

a, Schematic depiction of ATGL-mediated lipolysis and experimental design. b, Quantification of blood leukocytes in Atglfl/fl controls and AdipoqCreERT2Atglfl/fl mice (n = 8 Atglfl/fl, n = 7 AdipoqCreERT2Atglfl/fl, two-tailed Welch’s t test, two independent experiments). c, Quantification of bone marrow SLAM-LSK, LSK, CMP and GMP numbers in Atglfl/fl controls and AdipoqCreERT2Atglfl/fl mice (n = 8 Atglfl/fl, n = 7 AdipoqCreERT2Atglfl/fl, two-tailed Welch’s t test, two independent experiments). d, Flow plots of Brdu incorporation into LSK, SLAM-LSK, CMP and GMP in Atglfl/fl controls and AdipoqCreERT2Atglfl/fl mice. e, Quantification of LSK, SLAM-LSK, CMP and GMP proliferation in Atglfl/fl controls and AdipoqCreERT2Atglfl/fl mice (n = 8 Atglfl/fl, n = 7 AdipoqCreERT2Atglfl/fl, two-tailed Welch’s t test, two independent experiments). Data are displayed as mean ± SEM.

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Extended Data Fig. 6 Reduced hematopoiesis and myocardial myeloid cell content in AdipoqCreERT2Atglfl/fl mice.

a, Bone marrow adipocyte immunofluorescence images stained with perilipin-1 in Atglfl/fl versus AdipoqCreERT2Atglfl/fl mice 3 days after MI. b, Quantification of adipocyte size (n = 4 Atglfl/fl, n = 6 AdipoqCreERT2Atglfl/fl, two-tailed Welch’s t test, three independent experiments). c, Quantification of blood leukocytes in Atglfl/fl controls and AdipoqCreERT2Atglfl/fl mice 3 days after MI (n = 9 Atglfl/fl, n = 8 AdipoqCreERT2Atglfl/fl, two-tailed Welch’s t test, three independent experiments). d, Quantification of bone marrow leukocytes in Atglfl/fl controls and AdipoqCreERT2Atglfl/fl mice 3 days after MI (n = 9 Atglfl/fl, n = 9 AdipoqCreERT2Atglfl/fl, two-tailed Welch’s t test, three independent experiments). e, Flow plots of infiltrated leukocytes in the hearts of Atglfl/fl controls and AdipoqCreERT2Atglfl/fl. f, Quantification of macrophages, monocytes and neutrophils in the myocardium of Atglfl/fl controls and AdipoqCreERT2Atglfl/fl mice 3 days after MI (n = 9 Atglfl/fl, n = 9 AdipoqCreERT2Atglfl/fl, two-tailed Welch’s t test, three independent experiments). Data are displayed as mean ± SEM.

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Extended Data Fig. 7 Deletion of Atgl from adipocytes does not change 3 week post-MI outcomes.

a, Experimental Outline. b, Left ventricular morphology and function measured by cardiac magnetic resonance imaging (MRI) 3 weeks after coronary ligation in Atglfl/fl controls and AdipoqCreERT2Atglfl/fl mice (n = 9 and 10, Unpaired t-tests, two independent experiments). c, Quantification of blood leukocytes, monocytes, neutrophils (PMN) and B cells by flow cytometry 3 weeks after coronary ligation in Atglfl/fl controls and AdipoqCreERT2Atglfl/fl mice. (n = 6 and 7, Unpaired t-tests). Data are displayed as mean ± SEM.

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Extended Data Fig. 8 Flow cytometry gating strategies.

a, Gating strategy for lineage negative cells, used to gate on LK and LSK in Fig. 1g. b, Gating strategy for single live cells used for human HSPC gating. c, Gating strategy for blood leukocytes. The gating on specific cell types is detailed in extended data Fig. 1e.

Supplementary information

Reporting Summary

Supplementary Table 1

Differentially regulated genes ordered by ascending P value in flow-sorted bone marrow GMPs isolated from controls and mice on day 2 after MI, as assessed by RNA-seq. A Wald test was performed, and the P value was adjusted for multiple multiple comparisons based on the Benjamini–Hochberg algorithm to control the FDR.

Supplementary Table 2

Mass spectrometry data for Fig. 1f.

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Zhang, S., Paccalet, A., Rohde, D. et al. Bone marrow adipocytes fuel emergency hematopoiesis after myocardial infarction. Nat Cardiovasc Res 2, 1277–1290 (2023). https://doi.org/10.1038/s44161-023-00388-7

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