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Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells

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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Fig. 1: Therapeutic potential and challenges of cell- and EV-based therapies.
Fig. 2: iCMs secrete functional EVs.
Fig. 3: iCM-EVs are enriched in cardiac-specific miRNAs.
Fig. 4: Hydrogel patch sustainably released encapsulated EVs in a rat heart infarction model.
Fig. 5: iCM-EVs are non-arrhythmogenic and promote recovery of heart contractile function.
Fig. 6: iCM-EV-treatment-reduced infarct size and CM hypertrophy.
Fig. 7: iCM-EV treatment prevents apoptosis in the acutely infarcted heart.

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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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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.

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Correspondence to Gordana Vunjak-Novakovic.

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

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Liu, B., Lee, B.W., Nakanishi, K. et al. Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells. Nat Biomed Eng 2, 293–303 (2018). https://doi.org/10.1038/s41551-018-0229-7

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