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

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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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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