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Human pericardial fluid contains exosomes enriched with cardiovascular-expressed microRNAs and promotes therapeutic angiogenesis.

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journal contribution
posted on 2017-03-22, 16:13 authored by Cristina Beltrami, Marie Besnier, Saran Shantikumar, Andrew I. U. Shearn, Cha Rajakaruna, Abas Laftah, Fausto Sessa, Gaia Spinetti, Enrico Petretto, Gianni D. Angelini, Costanza Emanueli
The pericardial fluid (PF) is contained in the pericardial sac surrounding the heart. MicroRNA (miRNA) exchange via exosomes (endogenous nanoparticles) contributes to cell-to-cell communication. We investigated the hypotheses that the PF is enriched with miRNAs secreted by the heart and that it mediates vascular responses through exosome exchange of miRNAs. The study was developed using leftover material from aortic valve surgery. We found that in comparison with peripheral plasma, the PF contains exosomes enriched with miRNAs co-expressed in patients’ myocardium and vasculature. At a functional level, PF exosomes improved survival, proliferation, and networking of cultured endothelial cells (ECs) and restored the angiogenic capacity of ECs depleted (via Dicer silencing) of their endogenous miRNA content. Moreover, PF exosomes improved post-ischemic blood flow recovery and angiogenesis in mice. Mechanistically, (1) let-7b-5p is proangiogenic and inhibits its target gene, TGFBR1, in ECs; (2) PF exosomes transfer a functional let-7b-5p to ECs, thus reducing their TGFBR1 expression; and (3) let-7b-5p depletion in PF exosomes impairs the angiogenic response to these nanoparticles. Collectively, our data support the concept that PF exosomes orchestrate vascular repair via miRNA transfer.

Funding

This study was supported by the British Heart Foundation (BHF) program grant “MicroRNAs from Cardiac Surgery to Basic Science—and Back?” (RG/15/5/31446) and awards from the BHF Regenerative Medicine Centers (RM/13/2/30158) and the Leducq Transatlantic Network MIRVAD (13 CVD 02) (all to C.E.). Moreover, we received support from the National Institute of Heath Research (NIHR) through the Bristol Biomedical Research Unit (BRU) in Cardiovascular Medicine (to G.D.A.).

History

Citation

Molecular Therapy

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Health Sciences

Version

  • VoR (Version of Record)

Published in

Molecular Therapy

Publisher

Elsevier (Cell Press) for American Society of Gene and Cell Therapy

issn

1525-0016

eissn

1525-0024

Acceptance date

2016-12-15

Copyright date

2017

Available date

2017-03-22

Publisher version

http://www.sciencedirect.com/science/article/pii/S1525001617300035

Notes

Supplemental Information includes ten figures, three tables, raw data, and full unedited gel and can be found with this article online at http://dx.doi.org/10.1016/j.ymthe.2016.12.022.

Language

en

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