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Probing myeloid cell dynamics in ischaemic heart disease by nanotracer hot-spot imaging

Nature Nanotechnology volume 15, pages 398–405 (2020)Cite this article

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Abstract

Ischaemic heart disease evokes a complex immune response. However, tools to track the systemic behaviour and dynamics of leukocytes non-invasively in vivo are lacking. Here, we present a multimodal hot-spot imaging approach using an innovative high-density lipoprotein-derived nanotracer with a perfluoro-crown ether payload (19F-HDL) to allow myeloid cell tracking by 19F magnetic resonance imaging. The 19F-HDL nanotracer can additionally be labelled with zirconium-89 and fluorophores to detect myeloid cells by in vivo positron emission tomography imaging and optical modalities, respectively. Using our nanotracer in atherosclerotic mice with myocardial infarction, we observed rapid myeloid cell egress from the spleen and bone marrow by in vivo 19F-HDL magnetic resonance imaging. Concurrently, using ex vivo techniques, we showed that circulating pro-inflammatory myeloid cells accumulated in atherosclerotic plaques and at the myocardial infarct site. Our multimodality imaging approach is a valuable addition to the immunology toolbox, enabling the study of complex myeloid cell behaviour dynamically.

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Fig. 1: Nanotracer platform with multimodal evaluation in ischaemic heart disease.
Fig. 2: Developing and characterizing multimodal nanotracers.
Fig. 3: Characterization in atherosclerosis.
Fig. 4: Longitudinal evaluation of myeloid cell dynamics during atherosclerosis development.
Fig. 5: Multimodal imaging of myeloid cell egress from haematopoietic organs and recruitment to inflammatory sites in MI.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by De Drie Lichten Foundation in the Netherlands (M.L.S.); American Heart Association grant nos. 17PRE33660729 (M.L.S.) and 16SDG3139000 (C.P.M.); German Research Foundation grant nos. MA 7059/1 (A.M.) and HO 5953/1-1 (M.N.); National Heart, Lung, and Blood Institute grant nos. HL096576, HL117829, HL139598 and HL128264; the MGH Research Scholar Award (M.N. and F.K.S.); Dutch Applied and Engineering Sciences (TTW) grant no. 14716 (G.J.S); National Institutes of Health (NIH) grants: R01HL143814, R01HL144072, R01HL135878 and P01HL131478 (Z.A.F.); R01HL144072, R01CA220234 and P01HL131478 (W.J.M.M.); and the Netherlands Organisation for Scientific Research (NWO) grants: Vidi 91713324 and Vici 91818622 (W.J.M.M.).

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Authors and Affiliations

  1. BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Max L. Senders, Anu E. Meerwaldt, Mandy M. T. van Leent, Brenda L. Sanchez-Gaytan, Jan C. van de Voort, Yohana C. Toner, Alexander Maier, Emma D. Klein, Nathaniel A. T. Sullivan, Alexandros Marios Sofias, Hannah Groenen, Christopher Faries, Roderick S. Oosterwijk, Esther M. van Leeuwen, Francois Fay, Raphael Duivenvoorden, Carlos Pérez-Medina, Abraham J. P. Teunissen, Zahi A. Fayad, Claudia Calcagno, Gustav J. Strijkers & Willem J. M. Mulder

  2. Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

    Max L. Senders, Mandy M. T. van Leent & Willem J. M. Mulder

  3. Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht/Utrecht University, Utrecht, the Netherlands

    Anu E. Meerwaldt & Rick M. Dijkhuizen

  4. Instituto de Ciencias ICUAP, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico

    Brenda L. Sanchez-Gaytan

  5. Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway

    Alexandros Marios Sofias & Sjoerd Hak

  6. Institut Galien Paris Sud, Faculté de Pharmacie, CNRS, Université Paris-Sud, Université Paris-Saclay, Paris, France

    Francois Fay

  7. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Elena Chepurko & Lior Zangi

  8. Department of Radiology, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA

    Thomas Reiner

  9. Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands

    Raphael Duivenvoorden

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

    Filip K. Swirski & Matthias Nahrendorf

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

    Filip K. Swirski & Matthias Nahrendorf

  12. Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain

    Carlos Pérez-Medina

  13. Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

    Gustav J. Strijkers

  14. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Willem J. M. Mulder

  15. Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands

    Willem J. M. Mulder

Authors
  1. Max L. Senders
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Contributions

M.L.S. coordinated the experimental planning and execution. W.J.M.M. conceptualized and designed the study. A.J.P.T., B.L.S.-G., C.P.-M. and E.D.K. developed, synthesized, characterized and labelled the nanotracers. M.L.S., A.E.M., M.M.T.L., J.C.V., Y.C.T., A.M., E.D.K., N.A.T.S., A.M.S., H.G., C.F., R.S.O., E.M.L., F.F. and E.C. conducted the in vivo experiments. C.C., Z.A.F. and G.J.S. developed the imaging protocols. M.N. and F.K.S. developed the flow cytometry protocols and provided immunological insights. R.M.D., R.D. and L.Z. contributed expertise on cardiovascular disease mouse models. S.H. and T.R. designed nanotracer labelling strategies. M.L.S. and W.J.M.M. wrote the manuscript and M.L.S. produced the figures for initial submission. All authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Willem J. M. Mulder.

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The authors declare no competing interests.

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Peer review information Nature Nanotechnology thanks Jeff Bulte, Christian Schulz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Senders, M.L., Meerwaldt, A.E., van Leent, M.M.T. et al. Probing myeloid cell dynamics in ischaemic heart disease by nanotracer hot-spot imaging. Nat. Nanotechnol. 15, 398–405 (2020). https://doi.org/10.1038/s41565-020-0642-4

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