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Targeted repair of heart injury by stem cells fused with platelet nanovesicles

Nature Biomedical Engineering volume 2, pages 17–26 (2018)Cite this article

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Abstract

Stem cell transplantation, as used clinically, suffers from low retention and engraftment of the transplanted cells. Inspired by the ability of platelets to recruit stem cells to sites of injury on blood vessels, we hypothesized that platelets might enhance the vascular delivery of cardiac stem cells (CSCs) to sites of myocardial infarction injury. Here, we show that CSCs with platelet nanovesicles fused onto their surface membranes express platelet surface markers that are associated with platelet adhesion to injury sites. We also find that the modified CSCs selectively bind collagen-coated surfaces and endothelium-denuded rat aortas, and that in rat and porcine models of acute myocardial infarction the modified CSCs increase retention in the heart and reduce infarct size. Platelet-nanovesicle-fused CSCs thus possess the natural targeting and repairing ability of their parental cell types. This stem cell manipulation approach is fast, straightforward and safe, does not require genetic alteration of the cells, and should be generalizable to multiple cell types.

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Fig. 1: Platelet binding to myocardial infarction sites and the derivation of platelet nanovesicles.
Fig. 2: Generation and characterization of PNV-CSCs.
Fig. 3: The effects of PNV decoration on CSC viability and functions.
Fig. 4: PNV decoration promotes CSC binding to damaged rodent vasculatures.
Fig. 5: PNV decoration boosts CSC retention and therapeutic outcomes in rats with myocardial infarction.
Fig. 6: PNV-CSC therapy promotes myocyte proliferation and angiogenesis.
Fig. 7: The role of CD42b in targeting PNV-CSCs to MI injury.
Fig. 8: PNV decoration augments CSC retention in a porcine model of ischaemia/reperfusion.

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Acknowledgements

This work was supported by US National Institute of Health (HL123920 and HL137093), NC State University Chancellor’s Faculty Excellence Program, NC State Chancellor’s Innovation Fund, University of North Carolina General Assembly Research Opportunities Initiative grant and the National Natural Science Foundation of China (81370216, 81570274).

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  1. Junnan Tang, Teng Su, Ke Huang and Phuong-Uyen Dinh contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA

    Junnan Tang, Teng Su, Ke Huang, Phuong-Uyen Dinh, Adam Vandergriff, Michael T. Hensley, Jhon Cores, Tyler Allen, Deliang Shen & Ke Cheng

  2. Joint Department of Biomedical Engineering and Comparative Medicine Institute, University of North Carolina at Chapel Hill & North Carolina State University, Raleigh, NC, USA

    Junnan Tang, Teng Su, Adam Vandergriff, Michael T. Hensley, Jhon Cores, Erin Sproul, Emily Mihalko, Ashley Brown, Deliang Shen, Zhen Gu & Ke Cheng

  3. Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Junnan Tang, Deliang Shen & Jinying Zhang

  4. The Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu, China

    Zegen Wang & Ke Cheng

  5. Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan

    Taosheng Li

  6. Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Leonard J. Lobo

  7. Department of Clinical Sciences, North Carolina State University, Raleigh, NC, USA

    Laura Ruterbories & Alex Lynch

  8. Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Thomas G. Caranasos

  9. Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    George A. Stouffer

  10. Pharmacoengineering and Molecular Pharmaceutics Division, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Ke Cheng

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  1. Junnan Tang
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Contributions

J.T., T.S., K.H., P.-U.D. and K.C. designed the research, performed biochemical, cellular and animal experiments, analysed the data and drafted the paper. P.-U.D., Z.W., A.V., M.T.H., T.A., J.C., T.L., E.S., E.M., L.L., L.R., A.L., A.B., T.G.C., D.S., Z.G. and G.A.S. performed cellular and in vitro experiments, and/or provided comments to improve the paper. K.C. and J.Z. provided financial support. K.C. directed the research.

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Correspondence to Ke Cheng.

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Videos

Supplementary Video 1

Angiogram showing blood flow before ischaemia.

Supplementary Video 2

Angiogram showing the location of balloon inflation and blood flow during ischaemia.

Supplementary Video 3

Angiogram showing blood flow after ischaemia.

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Tang, J., Su, T., Huang, K. et al. Targeted repair of heart injury by stem cells fused with platelet nanovesicles. Nat Biomed Eng 2, 17–26 (2018). https://doi.org/10.1038/s41551-017-0182-x

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