Abstract

The ability of extracellular vesicles (EVs) to regulate a broad range of cellular processes has recently been exploited for the treatment of diseases. For example, EVs secreted by therapeutic cells injected into infarcted hearts can induce recovery through the delivery of cell-specific microRNAs. However, retention of the EVs and the therapeutic effects are short-lived. Here, we show that an engineered hydrogel patch capable of slowly releasing EVs secreted from cardiomyocytes (CMs) derived from induced pluripotent stem cells reduced arrhythmic burden, promoted ejection-fraction recovery, decreased CM apoptosis 24 h after infarction, and reduced infarct size and cell hypertrophy 4 weeks post-infarction when implanted onto infarcted rat hearts. We also show that EVs are enriched with cardiac-specific microRNAs known to modulate CM-specific processes. The extended delivery of EVs secreted from induced-pluripotent-stem-cell-derived CMs into the heart may help us to treat heart injury and to understand heart recovery.

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Acknowledgements

We thank M. Moore (Memorial Sloan Kettering Cancer Center) for making the particle-tracking instrument (NanoSight) available, and S. R. Ambati and A. Saxena (Memorial Sloan Kettering Cancer Center) for technical help. We thank Q. Li for performing animal surgeries, R. Liu and L. Zaurov for assistance with animal echocardiograms, and S. Halligan for coordinating the animal work. We thank D. Teles, N. Kim and A. Pluchinksky for assistance with the experiments. We thank B. Fine for valuable discussions on the manuscript. We gratefully acknowledge funding for this work by the NIH (HL076485, EB002520, EB17103 and GM007367), NYSTEM (C028119), the NIA (F30 AG047748) and the Lisa and Mark Schwartz Program for Reversing Heart Failure.

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Author notes

  1. These authors contributed equally: Bohao Liu, Benjamin W. Lee.

Affiliations

  1. College of Physicians and Surgeons, Columbia University, New York, NY, USA

    • Bohao Liu
    • , Benjamin W. Lee
    • , Rebecca Williamson
    •  & Jordan Metz
  2. Department of Medicine, Columbia University, New York, NY, USA

    • Bohao Liu
    • , Koki Nakanishi
    • , Mariko Kanai
    • , Shunichi Homma
    • , Veli K. Topkara
    •  & Gordana Vunjak-Novakovic
  3. Department of Biomedical Engineering, Columbia University, New York, NY, USA

    • Benjamin W. Lee
    • , Aranzazu Villasante
    • , Jinho Kim
    • , Lynn Bi
    •  & Gordana Vunjak-Novakovic
  4. Department of Pathology and Cell Biology, Columbia University, New York, NY, USA

    • Rebecca Williamson
    • , Kristy Brown
    •  & Gilbert Di Paolo
  5. Department of Systems Biology, Columbia University, New York, NY, USA

    • Jordan Metz
    •  & Peter A. Sims
  6. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA

    • Peter A. Sims

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Contributions

B.L., B.W.L., G.D.P., S.H., P.A.S., V.K.T. and G.V.-N. designed the study. B.L., B.W.L., K.N., A.V., R.W., J.K., M.K., L.B. and K.B. performed the experiments. B.L., B.W.L. and J.M. analysed the data. B.L., B.W.L., P.A.S., V.K.T. and G.V.-N. wrote the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Gordana Vunjak-Novakovic.

Supplementary information

  1. Supplementary Information

    Supplementary figures and tables

  2. Reporting Summary

  3. Supplementary Dataset

    Exosome miRNA sequencing, miRNA search targets, gene ontology, echocardiography data and correlation analysis.

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DOI

https://doi.org/10.1038/s41551-018-0229-7

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