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Exosome-eluting stents for vascular healing after ischaemic injury

Abstract

Drug-eluting stents implanted after ischaemic injury reduce the proliferation of endothelial cells and vascular smooth muscle cells and thus neointimal hyperplasia. However, the eluted drug also slows down the re-endothelialization process, delays arterial healing and can increase the risk of late restenosis. Here we show that stents releasing exosomes derived from mesenchymal stem cells in the presence of reactive oxygen species enhance vascular healing in rats with renal ischaemia-reperfusion injury, promoting endothelial cell tube formation and proliferation, and impairing the migration of smooth muscle cells. Compared with drug-eluting stents and bare-metal stents, the exosome-coated stents accelerated re-endothelialization and decreased in-stent restenosis 28 days after implantation. We also show that exosome-eluting stents implanted in the abdominal aorta of rats with unilateral hindlimb ischaemia regulated macrophage polarization, reduced local vascular and systemic inflammation, and promoted muscle tissue repair.

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Fig. 1: Fabrication and characterization of EES.
Fig. 2: In vitro ROS-trigged exosome release and biocompatibility of EES.
Fig. 3: EES promotes the proliferation and migration of endothelial cells but inhibits the migration of SMCs.
Fig. 4: Stenting in the abdominal aorta of rats.
Fig. 5: Neointimal formation with different stents.
Fig. 6: Local inflammation and immune-modulation effects of stent implantation.
Fig. 7: Restoration of blood flow and muscle repair in the ischaemic limbs of Apoe−/− rats after EES treatment.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, but are available for research purposes from the corresponding author on reasonable request. GeneQuery rat macrophage polarization markers qPCR array data are available on the NCBI database with the identifier GSE155793. ToF-SIMS, XPS and histopathological data are available on reasonable request.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (HL123920, HL137093, HL144002, HL146153, HL147357 and HL149940 to K.C.) and the American Heart Association (18TPA34230092 and 19EIA34660286 to K.C.). We thank the Analytical Instrumentation Facility at North Carolina State University (supported by the State of North Carolina and the National Science Foundation ECCS-1542015 and DMR-1726294). XPS and ToF-SIMS were performed and analysed at the Analytical Instrumentation Facility. Confocal imaging was performed at the Cellular and Molecular Imaging Facility at North Carolina State University.

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S.H. and K.C. designed the study and wrote the paper. Z.L. contributed to the stent modification. D.S. provided the technical and surgical support. D.Z. and K.H. contributed to the stent deployment and the hindlimb ischaemia model. Z.L., T.S., P.-U.D. and J.C. contributed to data analysis.

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Correspondence to Ke Cheng.

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Hu, S., Li, Z., Shen, D. et al. Exosome-eluting stents for vascular healing after ischaemic injury. Nat Biomed Eng (2021). https://doi.org/10.1038/s41551-021-00705-0

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